Compounds and methods for modulating ATXN1

ABSTRACT

Provided are compounds, methods, and pharmaceutical compositions for reducing the amount or activity of ATXN1 RNA in a cell or subject, and in certain instances reducing the amount of ATXN1 in a cell or subject. Such compounds, methods, and pharmaceutical compositions are useful to ameliorate at least one symptom or hallmark of a neurodegenerative disease. Such symptoms and hallmarks include gait and limb ataxia, cognitive impairments, difficulty with speaking and swallowing, atrophy of the cerebellum and brainstem in magnetic resonance imaging (MRI), neurochemical abnormalities in the cerebellum and brainstem detected via magnetic resonance spectroscopy (MRS), and death within 10-15 years of symptom onset. Such neurodegenerative diseases include Spinocerebellar ataxia type 1.

SEQUENCE LISTING

The present application is being filed along with a Sequence Listing in electronic format. The Sequence Listing is provided as a file entitled BIOL0355USC1SEQ_ST25.txt, created on May 20, 2022, which is 1.32 MB in size. The information in the electronic format of the sequence listing is incorporated herein by reference in its entirety.

FIELD

Provided are compounds, methods, and pharmaceutical compositions for reducing the amount or activity of ATXN1 RNA in a cell or subject, and in certain instances reducing the amount of ATXN1 protein in a cell or subject. Such compounds, methods, and pharmaceutical compositions are useful to ameliorate at least one symptom or hallmark of a neurodegenerative disease. Such symptoms and hallmarks include gait and limb ataxia, cognitive impairments, difficulty with speaking and swallowing, atrophy of the cerebellum and brainstem in magnetic resonance imaging (MRI), neurochemical abnormalities in the cerebellum and brainstem detected via magnetic resonance spectroscopy (MRS), and death within 10-15 years of symptom onset. Such neurodegenerative diseases include Spinocerebellar ataxia type 1.

BACKGROUND

Spinocerebellar ataxia type 1 (SCA1) is a progressive and fatal neurodegenerative disorder that affects 1-2/100,000 individuals worldwide. SCA1 is caused by an expanded CAG repeat in the coding region of gene encoding Ataxin-1, ATXN1. Accumulation of mutant Ataxin-1 protein leads to the degeneration of Purkinje cells and brainstem nuclei. Symptoms and hallmarks of SCA1 include gait and limb ataxia, cognitive impairments, difficulty with speaking and swallowing, atrophy of the cerebellum and brainstem in magnetic resonance imaging (MRI), neurochemical abnormalities in the cerebellum and brainstem detected via magnetic resonance spectroscopy (MRS), and death within 10-15 years of symptom onset (see, e.g., Ju, H., Kokubu, H., and Lim, J., Mol. Neurobiol. 50:866-874, 2014; Ortiz, J. P., Orr, H. T., in Polyglutamine Disorders, Nóbrega, C. and Almeida, L., eds., Advances in Exp. Med. And Biol., 1049: 135-145, 2018).

There are no specific therapies for SCA1, with current treatments being limited to supportive treatments for individual symptoms.

Currently there is a lack of acceptable options for treating neurodegenerative diseases such as SCA1. It is therefore an object herein to provide compounds, methods, and pharmaceutical compositions for the treatment of such diseases.

SUMMARY OF THE INVENTION

Provided herein are compounds, methods and pharmaceutical compositions for reducing the amount or activity of ATXN1 RNA, and in certain embodiments reducing the expression of ATXN1 protein in a cell or subject. In certain embodiments, the subject has a neurodegenerative disease. In certain embodiments, the subject has Spinocerebellar ataxia type 1 (SCA1). In certain embodiments, compounds useful for reducing the amount or activity of ATXN1 RNA are oligomeric compounds. In certain embodiments, compounds useful for reducing the amount or activity of ATXN1 RNA are modified oligonucleotides. In certain embodiments, compounds useful for decreasing expression of ATXN1 protein are oligomeric compounds. In certain embodiments, compounds useful for decreasing expression of ATXN1 protein are modified oligonucleotides.

Also provided are methods useful for ameliorating at least one symptom or hallmark of a neurodegenerative disease. In certain embodiments, the neurodegenerative disease is Spinocerebellar ataxia type 1. In certain embodiments, the symptom or hallmark includes gait and limb ataxia, cognitive impairments, difficulty with speaking and swallowing, atrophy of the cerebellum and brainstem in magnetic resonance imaging (MRI), neurochemical abnormalities in the cerebellum and brainstem detected via magnetic resonance spectroscopy (MRS), and death within 10-15 years of symptom onset.

DETAILED DESCRIPTION OF THE INVENTION

It is to be understood that both the foregoing general description and the following detailed description are exemplary and explanatory only and are not restrictive. Herein, the use of the singular includes the plural unless specifically stated otherwise. As used herein, the use of “or” means “and/or” unless stated otherwise. Furthermore, the use of the term “including” as well as other forms, such as “includes” and “included”, is not limiting. Also, terms such as “element” or “component” encompass both elements and components comprising one unit and elements and components that comprise more than one subunit, unless specifically stated otherwise.

The section headings used herein are for organizational purposes only and are not to be construed as limiting the subject matter described. All documents, or portions of documents, cited in this application, including, but not limited to, patents, patent applications, articles, books, treatises, and GenBank, ENSEMBL, and NCBI reference sequence records, are hereby expressly incorporated-by-reference for the portions of the document discussed herein, as well as in their entirety.

Definitions

Unless specific definitions are provided, the nomenclature used in connection with, and the procedures and techniques of, analytical chemistry, synthetic organic chemistry, and medicinal and pharmaceutical chemistry described herein are those well-known and commonly used in the art. Where permitted, all patents, applications, published applications and other publications and other data referred to throughout in the disclosure are incorporated by reference herein in their entirety.

Unless otherwise indicated, the following terms have the following meanings:

Definitions

As used herein, “2′-deoxynucleoside” means a nucleoside comprising a 2′-H(H) deoxyfuranosyl sugar moiety. In certain embodiments, a 2′-deoxynucleoside is a 2′-β-D-deoxynucleoside and comprises a 2′-β-D-deoxyribosyl sugar moiety, which has the β-D ribosyl configuration as found in naturally occurring deoxyribonucleic acids (DNA). In certain embodiments, a 2′-deoxynucleoside may comprise a modified nucleobase or may comprise an RNA nucleobase (uracil).

As used herein, “2′-MOE” means a 2′-OCH₂CH₂OCH₃ group in place of the 2′—OH group of a furanosyl sugar moiety. A “2′-MOE sugar moiety” means a sugar moiety with a 2′-OCH₂CH₂OCH₃ group in place of the 2′—OH group of a furanosyl sugar moiety. Unless otherwise indicated, a 2′-MOE sugar moiety is in the β-D-ribosyl configuration. “MOE” means O-methoxyethyl.

As used herein, “2′-MOE nucleoside” means a nucleoside comprising a 2′-MOE sugar moiety.

As used herein, “2′-OMe” means a 2′-OCH₃ group in place of the 2′—OH group of a furanosyl sugar moiety. A “2′-O-methyl sugar moiety” or “2′-OMe sugar moiety” means a sugar moiety with a 2′-OCH₃ group in place of the 2′-OH group of a furanosyl sugar moiety. Unless otherwise indicated, a 2′-OMe sugar moiety is in the β-D-ribosyl configuration.

As used herein, “2′-OMe nucleoside” means a nucleoside comprising a 2′-OMe sugar moiety.

As used herein, “2′-substituted nucleoside” means a nucleoside comprising a 2′-substituted sugar moiety. As used herein, “2′-substituted” in reference to a sugar moiety means a sugar moiety comprising at least one 2′-substituent group other than H or OH.

As used herein, “5-methyl cytosine” means a cytosine modified with a methyl group attached to the 5 position. A 5-methyl cytosine is a modified nucleobase.

As used herein, “administering” means providing a pharmaceutical agent to a subject.

As used herein, “antisense activity” means any detectable and/or measurable change attributable to the hybridization of an antisense compound to its target nucleic acid. In certain embodiments, antisense activity is a decrease in the amount or expression of a target nucleic acid or protein encoded by such target nucleic acid compared to target nucleic acid levels or target protein levels in the absence of the antisense compound.

As used herein, “antisense compound” means an oligomeric compound capable of achieving at least one antisense activity.

As used herein, “ameliorate” in reference to a treatment means improvement in at least one symptom relative to the same symptom in the absence of the treatment. In certain embodiments, amelioration is the reduction in the severity or frequency of a symptom or the delayed onset or slowing of progression in the severity or frequency of a symptom. In certain embodiments, the symptom or hallmark is gait and limb ataxia, cognitive impairments, difficulty with speaking and swallowing, atrophy of the cerebellum and brainstem in magnetic resonance imaging (MRI), neurochemical abnormalities in the cerebellum and brainstem detected via magnetic resonance spectroscopy (MRS), and death within 10-15 years of symptom onset.

As used herein, “bicyclic nucleoside” or “BNA” means a nucleoside comprising a bicyclic sugar moiety.

As used herein, “bicyclic sugar” or “bicyclic sugar moiety” means a modified sugar moiety comprising two rings, wherein the second ring is formed via a bridge connecting two of the atoms of the first ring thereby forming a bicyclic structure. In certain embodiments, the first ring of the bicyclic sugar moiety is a furanosyl moiety. In certain embodiments, the furanosyl sugar moiety is a ribosyl moiety. In certain embodiments, the bicyclic sugar moiety does not comprise a furanosyl moiety.

As used herein, “cleavable moiety” means a bond or group of atoms that is cleaved under physiological conditions, for example, inside a cell, an animal, or a human.

As used herein, “complementary” in reference to an oligonucleotide means that at least 70% of the nucleobases of the oligonucleotide or one or more portions thereof and the nucleobases of another nucleic acid or one or more portions thereof are capable of hydrogen bonding with one another when the nucleobase sequence of the oligonucleotide and the other nucleic acid are aligned in opposing directions. As used herein, complementary nucleobases means nucleobases that are capable of forming hydrogen bonds with one another. Complementary nucleobase pairs include adenine (A) and thymine (T), adenine (A) and uracil (U), cytosine (C) and guanine (G), 5-methyl cytosine (mC) and guanine (G). Complementary oligonucleotides and/or target nucleic acids need not have nucleobase complementarity at each nucleoside. Rather, some mismatches are tolerated. As used herein, “fully complementary” or “100% complementary” in reference to an oligonucleotide, or portion thereof, means that the oligonucleotide, or a portion thereof, is complementary to another oligonucleotide or target nucleic acid at each nucleobase of the shorter of the two oligonucleotides, or at each nucleoside if the oligonucleotides are the same length.

As used herein, “conjugate group” means a group of atoms that is directly or indirectly attached to an oligonucleotide. Conjugate groups include a conjugate moiety and a conjugate linker that attaches the conjugate moiety to the oligonucleotide.

As used herein, “conjugate linker” means a single bond or a group of atoms comprising at least one bond that connects a conjugate moiety to an oligonucleotide.

As used herein, “conjugate moiety” means a group of atoms that is attached to an oligonucleotide via a conjugate linker.

As used herein, “contiguous” in the context of an oligonucleotide refers to nucleosides, nucleobases, sugar moieties, or internucleoside linkages that are immediately adjacent to each other. For example, “contiguous nucleobases” means nucleobases that are immediately adjacent to each other in a sequence.

As used herein, “cEt” means a 4′ to 2′ bridge in place of the 2′OH-group of a ribosyl sugar moiety, wherein the bridge has the formula of 4′-CH(CH₃)—O-2′, and wherein the methyl group of the bridge is in the S configuration. A “cEt sugar moiety” is a bicyclic sugar moiety with a 4′ to 2′ bridge in place of the 2′OH-group of a ribosyl sugar moiety, wherein the bridge has the formula of 4′-CH(CH₃)—O-2′, and wherein the methyl group of the bridge is in the S configuration. “cEt” means constrained ethyl.

As used herein, “cEt nucleoside” means a nucleoside comprising a cEt sugar moiety. As used herein, “chirally enriched population” means a plurality of molecules of identical molecular formula, wherein the number or percentage of molecules within the population that contain a particular stereochemical configuration at a particular chiral center is greater than the number or percentage of molecules expected to contain the same particular stereochemical configuration at the same particular chiral center within the population if the particular chiral center were stereorandom. Chirally enriched populations of molecules having multiple chiral centers within each molecule may contain one or more stereorandom chiral centers. In certain embodiments, the molecules are modified oligonucleotides. In certain embodiments, the molecules are compounds comprising modified oligonucleotides.

As used herein, “chirally controlled” in reference to an internucleoside linkage means chirality at that linkage is enriched for a particular stereochemical configuration.

As used herein, “deoxy region” means a region of 5-12 contiguous nucleotides, wherein at least 70% of the nucleosides are 2′-β-D-deoxynucleosides. In certain embodiments, each nucleoside is selected from a 2′-β-D-deoxynucleoside, a bicyclic nucleoside, and a 2′-substituted nucleoside. In certain embodiments, a deoxy region supports RNase H activity. In certain embodiments, a deoxy region is the gap or internal region of a gapmer.

As used herein, “gapmer” means a modified oligonucleotide comprising an internal region having a plurality of nucleosides that support RNase H cleavage positioned between external regions having one or more nucleosides, wherein the nucleosides comprising the internal region are chemically distinct from the nucleoside or nucleosides comprising the external regions. The internal region may be referred to as the “gap” and the external regions may be referred to as the “wings.” The internal region is a deoxy region. The positions of the internal region or gap refer to the order of the nucleosides of the internal region and are counted starting from the 5′-end of the internal region. Unless otherwise indicated, “gapmer” refers to a sugar motif. In certain embodiments, each nucleoside of the gap is a 2′-β-D-deoxynucleoside. In certain embodiments, the gap comprises one 2′-substituted nucleoside at position 1, 2, 3, 4, or 5 of the gap, and the remainder of the nucleosides of the gap are 2′-β-D-deoxynucleosides. As used herein, the term “MOE gapmer” indicates a gapmer having a gap comprising 2′-β-D-deoxynucleosides and wings comprising 2′-MOE nucleosides. As used herein, the term “mixed wing gapmer” indicates a gapmer having wings comprising modified nucleosides comprising at least two different sugar modifications. Unless otherwise indicated, a gapmer may comprise one or more modified internucleoside linkages and/or modified nucleobases and such modifications do not necessarily follow the gapmer pattern of the sugar modifications.

As used herein, “hotspot region” is a range of nucleobases on a target nucleic acid that is amenable to oligomeric compound-mediated reduction of the amount or activity of the target nucleic acid.

As used herein, “hybridization” means the pairing or annealing of complementary oligonucleotides and/or nucleic acids. While not limited to a particular mechanism, the most common mechanism of hybridization involves hydrogen bonding, which may be Watson-Crick, Hoogsteen or reversed Hoogsteen hydrogen bonding, between complementary nucleobases.

As used herein, “internucleoside linkage” means the covalent linkage between contiguous nucleosides in an oligonucleotide. As used herein, “modified internucleoside linkage” means any internucleoside linkage other than a phosphodiester internucleoside linkage. “Phosphorothioate internucleoside linkage” is a modified internucleoside linkage in which one of the non-bridging oxygen atoms of a phosphodiester internucleoside linkage is replaced with a sulfur atom.

As used herein, “linker-nucleoside” means a nucleoside that links, either directly or indirectly, an oligonucleotide to a conjugate moiety. Linker-nucleosides are located within the conjugate linker of an oligomeric compound. Linker-nucleosides are not considered part of the oligonucleotide portion of an oligomeric compound even if they are contiguous with the oligonucleotide.

As used herein, “non-bicyclic modified sugar moiety” means a modified sugar moiety that comprises a modification, such as a substituent, that does not form a bridge between two atoms of the sugar to form a second ring.

As used herein, “mismatch” or “non-complementary” means a nucleobase of a first oligonucleotide that is not complementary with the corresponding nucleobase of a second oligonucleotide or target nucleic acid when the first and second oligonucleotide are aligned.

As used herein, “motif” means the pattern of unmodified and/or modified sugar moieties, nucleobases, and/or internucleoside linkages, in an oligonucleotide.

As used herein, “nucleobase” means an unmodified nucleobase or a modified nucleobase. As used herein an “unmodified nucleobase” is adenine (A), thymine (T), cytosine (C), uracil (U), or guanine (G). As used herein, a “modified nucleobase” is a group of atoms other than unmodified A, T, C, U, or G capable of pairing with at least one unmodified nucleobase. A “5-methyl cytosine” is a modified nucleobase. A universal base is a modified nucleobase that can pair with any one of the five unmodified nucleobases. As used herein, “nucleobase sequence” means the order of contiguous nucleobases in a target nucleic acid or oligonucleotide independent of any sugar or internucleoside linkage modification.

As used herein, “nucleoside” means a compound or a fragment of a compound comprising a nucleobase and a sugar moiety. The nucleobase and sugar moiety are each, independently, unmodified or modified. As used herein, “modified nucleoside” means a nucleoside comprising a modified nucleobase and/or a modified sugar moiety. Modified nucleosides include abasic nucleosides, which lack a nucleobase. “Linked nucleosides” are nucleosides that are connected in a contiguous sequence (i.e., no additional nucleosides are presented between those that are linked).

As used herein, “oligomeric compound” means an oligonucleotide and optionally one or more additional features, such as a conjugate group or terminal group. An oligomeric compound may be paired with a second oligomeric compound that is complementary to the first oligomeric compound or may be unpaired. A “singled-stranded oligomeric compound” is an unpaired oligomeric compound. The term “oligomeric duplex” means a duplex formed by two oligomeric compounds having complementary nucleobase sequences. Each oligomeric compound of an oligomeric duplex may be referred to as a “duplexed oligomeric compound.”

As used herein, “oligonucleotide” means a strand of linked nucleosides connected via internucleoside linkages, wherein each nucleoside and internucleoside linkage may be modified or unmodified. Unless otherwise indicated, oligonucleotides consist of 8-50 linked nucleosides. As used herein, “modified oligonucleotide” means an oligonucleotide, wherein at least one nucleoside or internucleoside linkage is modified. As used herein, “unmodified oligonucleotide” means an oligonucleotide that does not comprise any nucleoside modifications or internucleoside modifications.

As used herein, “pharmaceutically acceptable carrier or diluent” means any substance suitable for use in administering to a subject. Certain such carriers enable pharmaceutical compositions to be formulated as, for example, tablets, pills, dragees, capsules, liquids, gels, syrups, slurries, suspension and lozenges for the oral ingestion by a subject. In certain embodiments, a pharmaceutically acceptable carrier or diluent is sterile water, sterile saline, sterile buffer solution or sterile artificial cerebrospinal fluid.

As used herein, “pharmaceutically acceptable salts” means physiologically and pharmaceutically acceptable salts of compounds. Pharmaceutically acceptable salts retain the desired biological activity of the parent compound and do not impart undesired toxicological effects thereto.

As used herein, “pharmaceutical composition” means a mixture of substances suitable for administering to a subject. For example, a pharmaceutical composition may comprise an oligomeric compound and a sterile aqueous solution. In certain embodiments, a pharmaceutical composition shows activity in free uptake assay in certain cell lines.

As used herein, “prodrug” means a therapeutic agent in a form outside the body that is converted to a different form within a subject or cells thereof. Typically, conversion of a prodrug within the subject is facilitated by the action of an enzymes (e.g., endogenous or viral enzyme) or chemicals present in cells or tissues and/or by physiologic conditions.

As used herein, “reducing the amount or activity” refers to a reduction or blockade of the transcriptional expression or activity relative to the transcriptional expression or activity in an untreated or control sample and does not necessarily indicate a total elimination of transcriptional expression or activity.

As used herein, “RNA” means an RNA transcript and includes pre-mRNA and mature mRNA unless otherwise specified.

As used herein, “RNAi compound” means an antisense compound that acts, at least in part, through RISC or Ago2 to modulate a target nucleic acid and/or protein encoded by a target nucleic acid. RNAi compounds include, but are not limited to double-stranded siRNA, single-stranded RNA (ssRNA), and microRNA, including microRNA mimics. In certain embodiments, an RNAi compound modulates the amount, activity, and/or splicing of a target nucleic acid. The term RNAi compound excludes antisense compounds that act through RNase H.

As used herein, “self-complementary” in reference to an oligonucleotide means an oligonucleotide that at least partially hybridizes to itself.

As used herein, “standard in vitro assay” or “standard cell assay” means the assay described in Example 1 and reasonable variations thereof.

As used herein, “standard in vivo assay” means the assay described in Example 6 and reasonable variations thereof.

As used herein, “stereorandom chiral center” in the context of a population of molecules of identical molecular formula means a chiral center having a random stereochemical configuration. For example, in a population of molecules comprising a stereorandom chiral center, the number of molecules having the (S) configuration of the stereorandom chiral center may be but is not necessarily the same as the number of molecules having the (R) configuration of the stereorandom chiral center. The stereochemical configuration of a chiral center is considered random when it is the result of a synthetic method that is not designed to control the stereochemical configuration. In certain embodiments, a stereorandom chiral center is a stereorandom phosphorothioate internucleoside linkage.

As used herein, “subject” means a human or non-human animal.

As used herein, “sugar moiety” means an unmodified sugar moiety or a modified sugar moiety. As used herein, “unmodified sugar moiety” means a 2′-OH(H) β-D-ribosyl moiety, as found in RNA (an “unmodified RNA sugar moiety”), or a 2′-H(H) β-D-deoxyribosyl sugar moiety, as found in DNA (an “unmodified DNA sugar moiety”). Unmodified sugar moieties have one hydrogen at each of the 1′, 3′, and 4′ positions, an oxygen at the 3′ position, and two hydrogens at the 5′ position. As used herein, “modified sugar moiety” or “modified sugar” means a modified furanosyl sugar moiety or a sugar surrogate.

As used herein, “sugar surrogate” means a modified sugar moiety having other than a furanosyl moiety that can link a nucleobase to another group, such as an internucleoside linkage, conjugate group, or terminal group in an oligonucleotide. Modified nucleosides comprising sugar surrogates can be incorporated into one or more positions within an oligonucleotide and such oligonucleotides are capable of hybridizing to complementary oligomeric compounds or target nucleic acids.

As used herein, “symptom or hallmark” means any physical feature or test result that indicates the existence or extent of a disease or disorder. In certain embodiments, a symptom is apparent to a subject or to a medical professional examining or testing said subject. In certain embodiments, a hallmark is apparent upon invasive diagnostic testing, including, but not limited to, post-mortem tests. In certain embodiments, a hallmark is apparent on a brain MRI scan.

As used herein, “target nucleic acid” and “target RNA” mean a nucleic acid that an antisense compound is designed to affect.

As used herein, “target region” means a portion of a target nucleic acid to which an oligomeric compound is designed to hybridize.

As used herein, “terminal group” means a chemical group or group of atoms that is covalently linked to a terminus of an oligonucleotide.

As used herein, “therapeutically effective amount” means an amount of a pharmaceutical agent that provides a therapeutic benefit to a subject. For example, a therapeutically effective amount improves a symptom or hallmark of a disease.

CERTAIN EMBODIMENTS

The present disclosure provides the following non-limiting numbered embodiments:

-   -   Embodiment 1. An oligomeric compound comprising a modified         oligonucleotide consisting of 12 to 30 linked nucleosides         wherein the nucleobase sequence of the modified oligonucleotide         is at least 90% complementary to an equal length portion of an         ATXN1 nucleic acid, and wherein the modified oligonucleotide         comprises at least one modification selected from a modified         sugar moiety and a modified internucleoside linkage.     -   Embodiment 2. An oligomeric compound comprising a modified         oligonucleotide consisting of 12 to 30 linked nucleosides and         having a nucleobase sequence comprising at least 12, 13, 14, 15,         16, 17, 18, 19, or 20 contiguous nucleobases of any of SEQ ID         NOs: 22-3624 or 3655.     -   Embodiment 3. An oligomeric compound comprising a modified         oligonucleotide consisting of 12 to 30 linked nucleosides and         having a nucleobase sequence comprising at least 12, 13, 14, 15,         16, or 17 contiguous nucleobases of any of SEQ ID NOs: 3625-3654         or 3656-3669.     -   Embodiment 4. An oligomeric compound comprising a modified         oligonucleotide consisting of 12 to 30 linked nucleosides and         having a nucleobase sequence comprising at least 8, at least 9,         at least 10, at least 11, at least 12, at least 13, at least 14,         at least 15, at least 16, at least 17, at least 18, at least 19,         or at least 20 contiguous nucleobases complementary to:         -   an equal length portion of nucleobases 5472-5552 of SEQ ID             NO: 1;         -   an equal length portion of nucleobases 5906-6005 of SEQ ID             NO: 1;         -   an equal length portion of nucleobases 7868-7911 of SEQ ID             NO: 1;         -   an equal length portion of nucleobases 8481-8514 of SEQ ID             NO: 1; or         -   an equal length portion of nucleobases 446679-446706 of SEQ             ID NO: 2.     -   Embodiment 5. An oligomeric compound comprising a modified         oligonucleotide consisting of 12 to 30 linked nucleosides and         having a nucleobase sequence comprising at least 8, at least 9,         at least 10, at least 11, at least 12, at least 13, at least 14,         at least 15, at least 16, or at least 17 contiguous nucleobases         of a sequence selected from:         -   SEQ ID NOs: 196, 274, 352, 430, 508, 2578, 2655, 2732, 2809,             2886, 2963, 3121, 3122, 3190, 3191, 3192, 3262, 3330, 3331,             3332, 3401, 3402, 3575, 3577, 3620, 3624, 3638-3640,             3653-3655, 3662, 3665, 3669;         -   SEQ ID Nos: 42, 120, 198, 276, 509, 587, 2502, 2579, 2656,             2733, 2810, 2887, 2964, 3585, 3588-3590, 3615, 3618, 3622,             3657, 3660, 3661, 3663, 3664, 3666-3668;         -   SEQ ID Nos: 48, 126, 2044, 2121;         -   SEQ ID Nos: 128, 206, 284, 1045, 1122, 1199, and 1276; or         -   SEQ ID Nos: 2475, 2552, 2629, 2706, 2783, 3627-3630, 3644.     -   Embodiment 6. The oligomeric compound of any of embodiments 1-5,         wherein the modified oligonucleotide has a nucleobase sequence         that is at least 80%, 85%, 90%, 95%, or 100% complementary to         the nucleobase sequence of SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID         NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, or SEQ ID NO: 6 when measured         across the entire nucleobase sequence of the modified         oligonucleotide.     -   Embodiment 7. The oligomeric compound of any of embodiments 1-6,         wherein the modified oligonucleotide comprises at least one         modified nucleoside.     -   Embodiment 8. The oligomeric compound of embodiment 7, wherein         the modified oligonucleotide comprises at least one modified         nucleoside comprising a modified sugar moiety.     -   Embodiment 9. The oligomeric compound of embodiment 8, wherein         the modified oligonucleotide comprises at least one modified         nucleoside comprising a bicyclic sugar moiety.     -   Embodiment 10. The oligomeric compound of embodiment 9, wherein         the modified oligonucleotide comprises at least one modified         nucleoside comprising a bicyclic sugar moiety having a 2′-4′         bridge, wherein the 2′-4′ bridge is selected from —O—CH₂—; and         —O—CH(CH₃)—.     -   Embodiment 11. The oligomeric compound of any of embodiments         7-10, wherein the modified oligonucleotide comprises at least         one modified nucleoside comprising a non-bicyclic modified sugar         moiety.     -   Embodiment 12. The oligomeric compound of embodiment 11, wherein         the non-bicyclic modified sugar moiety is a 2′-MOE sugar moiety         or 2′-OMe modified sugar moiety.     -   Embodiment 13. The oligomeric compound of any of embodiments         7-8, wherein the modified oligonucleotide comprises at least one         modified nucleoside comprising a sugar surrogate.     -   Embodiment 14. The oligomeric compound of embodiment 13, wherein         the modified oligonucleotide comprises at least one modified         nucleoside comprising a sugar surrogate selected from morpholino         and PNA.     -   Embodiment 15. The oligomeric compound of any of embodiments 1-8         or 11-14, wherein the modified oligonucleotide does not comprise         a bicyclic sugar moiety.     -   Embodiment 16. The oligomeric compound of any of embodiments         1-15, wherein the modified oligonucleotide is a gapmer.     -   Embodiment 17. The oligomeric compound of any of embodiments         1-16, wherein the modified oligonucleotide has a sugar motif         comprising:         -   a 5′-region consisting of 1-6 linked 5′-region nucleosides;         -   a central region consisting of 6-10 linked central region             nucleosides; and         -   a 3′-region consisting of 1-6 linked 3′-region nucleosides;             wherein         -   each of the 5′-region nucleosides and each of the 3′-region             nucleosides comprises a modified sugar moiety and each of             the central region nucleosides comprises a 2′-deoxyfuranosyl             sugar moiety.     -   Embodiment 18. The oligomeric compound of embodiment 17, wherein         the modified oligonucleotide has a sugar motif comprising:         -   a 5′-region consisting of 6 linked 5′-region nucleosides;         -   a central region consisting of 10 linked central region             nucleosides; and         -   a 3′-region consisting of 4 linked 3′-region nucleosides;             wherein         -   each of the 5′-region nucleosides and each of the 3′-region             nucleosides is a 2′-MOE nucleoside, and each of the central             region nucleosides is a 2′-β-D-deoxynucleoside.     -   Embodiment 19. The oligomeric compound of embodiment 17, wherein         the modified oligonucleotide has a sugar motif comprising:         -   a 5′-region consisting of 5 linked 5′-region nucleosides;         -   a central region consisting of 10 linked central region             nucleosides; and         -   a 3′-region consisting of 5 linked 3′-region nucleosides;             wherein         -   each of the 5′-region nucleosides and each of the 3′-region             nucleosides is a 2′-MOE nucleoside, and each of the central             region nucleosides is a 2′-β-D-deoxynucleoside.     -   Embodiment 20. The oligomeric compound of embodiment 17, wherein         the modified oligonucleotide has         -   a 5′-region consisting of 5 linked 5′-region nucleosides;         -   a central region consisting of 8 linked central region             nucleosides; and         -   a 3′-region consisting of 4 linked 3′-region nucleosides;             wherein         -   each of the 5′-region nucleosides and each of the 3′-region             nucleosides comprises a is a 2′-MOE nucleoside, and each of             the central region nucleosides is a 2′-β-D-deoxynucleoside.     -   Embodiment 21. The oligomeric compound of embodiment 17, wherein         the modified oligonucleotide has         -   a 5′-region consisting of 5 linked 5′-region nucleosides;         -   a central region consisting of 8 linked central region             nucleosides; and         -   a 3′-region consisting of 4 linked 3′-region nucleosides;             wherein         -   each of the 5′-region nucleosides comprises a 2′-MOE sugar             moiety, each of the 3′-region nucleosides is selected from a             2′-MOE nucleoside and a cEt nucleoside, and each of the             central region nucleosides comprises a             2′-β-D-deoxynucleoside.     -   Embodiment 22. The oligomeric compound of any of embodiments         1-16, wherein the modified oligonucleotide has a sugar motif         comprising:         -   a 5′-region consisting of 1-6 linked 5′-region nucleosides;         -   a central region consisting of 6-10 linked central region             nucleosides; and         -   a 3′-region consisting of 1-6 linked 3′-region nucleosides;             wherein         -   each of the 5′-region nucleosides and each of the 3′-region             nucleosides comprises a modified sugar moiety,         -   and the central region has the following formula:             (Nd)(Nx)(Nd)n         -   wherein Nx is a 2′-OMe nucleoside and each Nd is a             2′-β-D-deoxynucleoside; and n is from 6 to 8.     -   Embodiment 23. The oligomeric compound of any of embodiments         1-16, wherein the modified oligonucleotide has a sugar motif         comprising:         -   a 5′-region consisting of 5 linked 5′-region nucleosides;         -   a central region consisting of 6-10 linked central region             nucleosides; and         -   a 3′-region consisting of 4 linked 3′-region nucleosides;             wherein         -   each of the 5′-region nucleosides and each of the 3′-region             nucleosides is selected from a 2′-MOE nucleoside and a cEt             nucleoside,         -   and the central region has the following formula:             (Nd)(Nx)(Nd)n         -   wherein Nx is a 2′-OMe nucleoside and each Nd is a             2′-β-D-deoxynucleoside; and n is 7.     -   Embodiment 24. The oligomeric compound of any of embodiments         1-23, wherein the modified oligonucleotide comprises at least         one modified internucleoside linkage.     -   Embodiment 25. The oligomeric compound of embodiment 24, wherein         each internucleoside linkage of the modified oligonucleotide is         a modified internucleoside linkage.     -   Embodiment 26. The oligomeric compound of embodiment 24 or 25         wherein the modified internucleoside linkage is a         phosphorothioate internucleoside linkage.     -   Embodiment 27. The oligomeric compound of embodiment 24 or 26         wherein the modified oligonucleotide comprises at least one         phosphodiester internucleoside linkage.     -   Embodiment 28. The oligomeric compound of any of embodiments 24,         26, or 27, wherein each internucleoside linkage is independently         selected from a phosphodiester internucleoside linkage or a         phosphorothioate internucleoside linkage.     -   Embodiment 29. The oligomeric compound of embodiments 1-24 or         26-28, wherein the modified oligonucleotide has an         internucleoside linkage motif selected from among:         sooosssssssssssooss, sssosssssssssssosss, sssosssssssssoss, or         sooooossssssssssoss; wherein,         -   s=a phosphorothioate internucleoside linkage and o=a             phosphodiester internucleoside linkage.     -   Embodiment 30. The oligomeric compound of any of embodiments         1-29, wherein the modified oligonucleotide comprises a modified         nucleobase.     -   Embodiment 31. The oligomeric compound of embodiment 30, wherein         the modified nucleobase is a 5-methyl cytosine.     -   Embodiment 32. The oligomeric compound of any of embodiments         1-31, wherein the modified oligonucleotide consists of 12-30,         12-22, 12-20, 14-18, 16-18, 14-20, 15-17, 15-25, 16-20, or 17-20         linked nucleosides.     -   Embodiment 33. The oligomeric compound of any of embodiments         1-2, 4-19, 22 or 24-31, wherein the modified oligonucleotide         consists of 18-22 or 18-20 linked nucleosides.     -   Embodiment 34. The oligomeric compound of any of embodiments         1-17 or 20-32, wherein the modified oligonucleotide consists of         17 linked nucleosides.     -   Embodiment 35. The oligomeric compound of any of embodiments         1-2, 4-19, 22 or 24-31, wherein the modified oligonucleotide         consists of 20 linked nucleosides.     -   Embodiment 36. The oligomeric compound of any of embodiments         1-35, consisting of the modified oligonucleotide.     -   Embodiment 37. The oligomeric compound of any of embodiments         1-35, comprising a conjugate group comprising a conjugate moiety         and a conjugate linker.     -   Embodiment 38. The oligomeric compound of embodiment 37, wherein         the conjugate linker consists of a single bond.     -   Embodiment 39. The oligomeric compound of embodiment 37, wherein         the conjugate linker is cleavable.     -   Embodiment 40. The oligomeric compound of embodiment 37, wherein         the conjugate linker comprises 1-3 linker-nucleosides.     -   Embodiment 41. The oligomeric compound of any of embodiments         37-40, wherein the conjugate group is attached to the modified         oligonucleotide at the 5′-end of the modified oligonucleotide.     -   Embodiment 42. The oligomeric compound of any of embodiments         37-40, wherein the conjugate group is attached to the modified         oligonucleotide at the 3′-end of the modified oligonucleotide.     -   Embodiment 43. The oligomeric compound of any of embodiments         1-35 or 37-42, comprising a terminal group.     -   Embodiment 44. The oligomeric compound of any of embodiments         1-43 wherein the oligomeric compound is a singled-stranded         oligomeric compound.     -   Embodiment 45. The oligomeric compound of any of embodiments         1-39 or 41-42, wherein the oligomeric compound does not comprise         linker-nucleosides.     -   Embodiment 46. An oligomeric duplex comprising an oligomeric         compound of any of embodiments 1-43 or 45.     -   Embodiment 47. An antisense compound comprising or consisting of         an oligomeric compound of any of embodiments 1-45 or an         oligomeric duplex of embodiment 46.     -   Embodiment 48. A pharmaceutical composition comprising an         oligomeric compound of any of embodiments 1-45 or an oligomeric         duplex of embodiment 46 and a pharmaceutically acceptable         carrier or diluent.     -   Embodiment 49. The pharmaceutical composition of embodiment 48,         wherein the pharmaceutically acceptable diluent is artificial         cerebral spinal fluid.     -   Embodiment 50. The pharmaceutical composition of embodiment 49,         wherein the pharmaceutical composition consists essentially of         the modified oligonucleotide and artificial cerebral spinal         fluid.     -   Embodiment 51. A method comprising administering to a subject a         pharmaceutical composition of any of embodiments 48-50.     -   Embodiment 52. A method of treating a disease associated with         ATXN1 comprising administering to an individual having or at         risk for developing a disease associated with ATXN1 a         therapeutically effective amount of a pharmaceutical composition         according to any of embodiments 48-50; and thereby treating the         disease associated with ATXN1.     -   Embodiment 53. The method of embodiment 52, wherein the         ATXN1-associated disease is Spinocerebellar ataxia type 1.     -   Embodiment 54. The method of any of embodiments 51-52, wherein         at least one symptom or hallmark of the ATXN1-associated disease         is ameliorated.     -   Embodiment 55. The method of embodiment 54, wherein the symptom         or hallmark is gait or limb ataxia, cognitive impairments,         difficulty with speaking or swallowing, atrophy of the         cerebellum and/or brainstem in magnetic resonance imaging (MRI),         neurochemical abnormalities in the cerebellum and/or brainstem         detected via magnetic resonance spectroscopy (MRS), or death         within 10-15 years of symptom onset.     -   Embodiment 56. The method of any of embodiments 51-53, wherein         ATXN1 levels in the individual are reduced.     -   Embodiment 57. A modified oligonucleotide according to the         following chemical structure:

or a salt thereof.

-   -   Embodiment 58. A modified oligonucleotide according to the         following chemical structure:

or a salt thereof.

-   -   Embodiment 59. A modified oligonucleotide according to the         following chemical structure:

or a salt thereof.

-   -   Embodiment 60. A modified oligonucleotide according to the         following chemical structure:

or a salt thereof.

-   -   Embodiment 61. A modified oligonucleotide according to the         following chemical structure:

or a salt thereof.

-   -   Embodiment 62. A modified oligonucleotide according to the         following chemical structure:

or a salt thereof.

-   -   Embodiment 63. A modified oligonucleotide according to the         following chemical structure:

-   -   Embodiment 64. A modified oligonucleotide according to the         following chemical structure:

-   -   Embodiment 65. A modified oligonucleotide according to the         following chemical structure:

-   -   Embodiment 66. A modified oligonucleotide according to the         following chemical structure:

-   -   Embodiment 67. A modified oligonucleotide according to the         following chemical structure:

-   -   Embodiment 68. A modified oligonucleotide according to the         following chemical structure:

-   -   Embodiment 69. The modified oligonucleotide of embodiment 57-62,         which is a sodium salt or a potassium salt.     -   Embodiment 70. A compound comprising a modified oligonucleotide         according to the following chemical notation:         -   Ges ^(m)Ceo Aeo ^(m)Ceo Ges Gds Tds Ads Tds Tds Ads Gds Tds             Gds Tds ^(m)Ceo Teo Tes ^(m)Ces Ae (SEQ ID NO: 126),             wherein,             -   A=an adenine nucleobase,             -   ^(m)C=a 5-methyl cytosine nucleobase,             -   G=a guanine nucleobase,             -   T=a thymine nucleobase,             -   e=a 2′-MOE sugar moiety,             -   d=a 2′-β-D deoxyribosyl sugar moiety,             -   s=a phosphorothioate internucleoside linkage, and             -   o=a phosphodiester internucleoside linkage.     -   Embodiment 71. A compound comprising a modified oligonucleotide         according to the following chemical notation:         -   Ges ^(m)Ceo Teo Teo ^(m)Ces Tds ^(m)Cds Ads Ads Ads Tds             ^(m)Cds Ads Gds Gds Teo Geo Tes Aes ^(m)Ce (SEQ ID NO:             1045), wherein,             -   A=an adenine nucleobase,             -   ^(m)C=a 5-methyl cytosine nucleobase,             -   G=a guanine nucleobase,             -   T=a thymine nucleobase,             -   e=a 2′-MOE sugar moiety,             -   d=a 2′-β-D deoxyribosyl sugar moiety,             -   s=a phosphorothioate internucleoside linkage, and             -   o=a phosphodiester internucleoside linkage.     -   Embodiment 72. A compound comprising a modified oligonucleotide         according to the following chemical notation:         -   Ges ^(m)Ceo ^(m)Ceo Teo Tes Tds Ads Tds Ads Ads ^(m)Cds Tds             Tds Tds Tds ^(m)Ceo Teo Tes Tes ^(m)Ce (SEQ ID NO: 2552),             wherein,             -   A=an adenine nucleobase,             -   ^(m)C=a 5-methyl cytosine nucleobase,             -   G=a guanine nucleobase,             -   T=a thymine nucleobase,             -   e=a 2′-MOE sugar moiety,             -   d=a 2′-β-D deoxyribosyl sugar moiety,             -   s=a phosphorothioate internucleoside linkage, and             -   o=a phosphodiester internucleoside linkage.     -   Embodiment 73. A compound comprising a modified oligonucleotide         according to the following chemical notation:         -   Tes Teo ^(m)Ceo Aeo Ges Tds Tds Tds Ads Gds Tds Tds Gds             ^(m)Cds Ads Geo ^(m)Ceo ^(m)Ces Aes Te (SEQ ID NO: 3190),             wherein,             -   A=an adenine nucleobase,             -   ^(m)C=a 5-methyl cytosine nucleobase,             -   G=a guanine nucleobase,             -   T=a thymine nucleobase,             -   e=a 2′-MOE sugar moiety,             -   d=a 2′-β-D deoxyribosyl sugar moiety,             -   s=a phosphorothioate internucleoside linkage, and             -   o=a phosphodiester internucleoside linkage.     -   Embodiment 74. A compound comprising a modified oligonucleotide         according to the following chemical notation:         -   ^(m)Ces ^(m)Ceo ^(m)Ceo Geo Tes Ads Tds Tds ^(m)Cds ^(m)Cds             Tds ^(m)Cds Tds Tds Ads ^(m)Ceo ^(m)Ceo Aes Tes ^(m)Ce (SEQ             ID NO: 3590), wherein,             -   A=an adenine nucleobase,             -   ^(m)C=a 5-methyl cytosine nucleobase,             -   G=a guanine nucleobase,             -   T=a thymine nucleobase,             -   e=a 2′-MOE sugar moiety,             -   d=a 2′-β-D deoxyribosyl sugar moiety,             -   s=a phosphorothioate internucleoside linkage, and             -   o=a phosphodiester internucleoside linkage.     -   Embodiment 75. A compound comprising a modified oligonucleotide         according to the following chemical notation:         -   Tes ^(m)Ces Aes Geo Tes Tds Tds Ads Gds Tds Tds Gds ^(m)Cds             Aeo Ges ^(m)Ces ^(m)Ce (SEQ ID NO: 3638), wherein,             -   A=an adenine nucleobase,             -   ^(m)C=a 5-methyl cytosine nucleobase,             -   G=a guanine nucleobase,             -   T=a thymine nucleobase,             -   e=a 2′-MOE sugar moiety,             -   d=a 2′-β-D deoxyribosyl sugar moiety,             -   s=a phosphorothioate internucleoside linkage, and             -   o=a phosphodiester internucleoside linkage.     -   Embodiment 76. The compound of any of embodiments 73-78,         comprising the modified oligonucleotide covalently linked to a         conjugate group.     -   Embodiment 77. A chirally enriched population of modified         oligonucleotides of any of embodiments 57-68, wherein the         population is enriched for modified oligonucleotides comprising         at least one particular phosphorothioate internucleoside linkage         having a particular stereochemical configuration.     -   Embodiment 78. The chirally enriched population of embodiment         77, wherein the population is enriched for modified         oligonucleotides comprising at least one particular         phosphorothioate internucleoside linkage having the (Sp) or (Rp)         configuration.     -   Embodiment 79. The chirally enriched population of embodiment         77, wherein the population is enriched for modified         oligonucleotides having a particular, independently selected         stereochemical configuration at each phosphorothioate         internucleoside linkage.     -   Embodiment 80. The chirally enriched population of embodiment         77, wherein the population is enriched for modified         oligonucleotides having the (Rp) configuration at one particular         phosphorothioate internucleoside linkage and the (Sp)         configuration at each of the remaining phosphorothioate         internucleoside linkages.     -   Embodiment 81. The chirally enriched population of embodiment 77         wherein the population is enriched for modified oligonucleotides         having at least 3 contiguous phosphorothioate internucleoside         linkages in the Sp, Sp, and Rp configurations, in the 5′ to 3′         direction.     -   Embodiment 82. A population of modified oligonucleotides of any         of embodiments 57-68, wherein all of the phosphorothioate         internucleoside linkages of the modified oligonucleotide are         stereorandom.     -   Embodiment 83. A pharmaceutical composition comprising the         population of modified oligonucleotides of any of embodiments         77-82 and a pharmaceutically acceptable diluent or carrier.     -   Embodiment 84. A pharmaceutical composition of any of         embodiments 62-75, and a pharmaceutically acceptable diluent or         carrier.     -   Embodiment 85. The pharmaceutical composition of embodiment 84,         wherein the pharmaceutically acceptable diluent is artificial         cerebrospinal fluid or phosphate-buffered saline.     -   Embodiment 86. The pharmaceutical composition of embodiment 85,         wherein the pharmaceutical composition consists essentially of         the modified oligonucleotide and artificial cerebrospinal fluid         or phosphate-buffered saline.     -   Embodiment 87. An oligomeric compound comprising a modified         oligonucleotide consisting of 12 to 30 linked nucleosides         wherein the nucleobase sequence of the modified oligonucleotide         is at least 80% complementary to an equal length portion of an         ATXN1 nucleic acid, and wherein the modified oligonucleotide         comprises at least one modification selected from a modified         sugar moiety and a modified internucleoside linkage.     -   Embodiment 88. The oligomeric compound of embodiment 87, wherein         the ATXN1 nucleic acid has the nucleobase sequence of any of SEQ         ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO:         5, or SEQ ID NO: 6.     -   Embodiment 89. The oligomeric compound of embodiment 87 or         embodiment 88, wherein the nucleobase sequence of the modified         oligonucleotide is at least 80% complementary to an equal length         portion within nucleobases:         -   an equal length portion of nucleobases 5472-5552 of SEQ ID             NO: 1;         -   an equal length portion of nucleobases 5906-6005 of SEQ ID             NO: 1;         -   an equal length portion of nucleobases 7868-7911 of SEQ ID             NO: 1;         -   an equal length portion of nucleobases 8481-8514 of SEQ ID             NO: 1; or         -   an equal length portion of nucleobases 446679-446706 of SEQ             ID NO: 2.     -   Embodiment 90. The oligomeric compound of any of embodiments         87-89, wherein the nucleobase sequence of the modified         oligonucleotide is at least 80% complementary to an equal length         portion within nucleobases:         -   an equal length portion of nucleobases 5489-5508 of SEQ ID             NO: 1;         -   an equal length portion of nucleobases 5491-5507 of SEQ ID             NO: 1;         -   an equal length portion of nucleobases 5912-5931 of SEQ ID             NO: 1;         -   an equal length portion of nucleobases 7892-7911 of SEQ ID             NO: 1;         -   an equal length portion of nucleobases 8481-8500 of SEQ ID             NO: 1; or         -   an equal length portion of nucleobases 446680-446699 of SEQ             ID NO: 2.     -   Embodiment 91. The oligomeric compound of any of embodiments         87-90, wherein the nucleobase sequence of the modified         oligonucleotide is at least 85%, at least 90%, at least 95%, or         100% complementary to an equal length portion of the ATXN1         nucleic acid.     -   Embodiment 92. An oligomeric compound comprising a modified         oligonucleotide consisting of 12 to 30 linked nucleosides,         wherein the modified oligonucleotide has a nucleobase sequence         comprising at least 12, 13, 14, 15, 16, 17, 18, 19, or 20         contiguous nucleobases of any of SEQ ID NOs: 22-3624 or 3655.     -   Embodiment 93. An oligomeric compound comprising a modified         oligonucleotide consisting of 12 to 30 linked nucleosides,         wherein the modified oligonucleotide has a nucleobase sequence         comprising at least 12, 13, 14, 15, 16, or 17 contiguous         nucleobases of any of SEQ ID NOs: 3625-3654 or 3656-3669.     -   Embodiment 94. The oligomeric compound of embodiment 92 or 93,         wherein the modified oligonucleotide has a nucleobase sequence         comprising the nucleobase sequence of any of SEQ ID NO: 22-3669.     -   Embodiment 95. The oligomeric compound of embodiment 94, wherein         the modified oligonucleotide has a nucleobase sequence         consisting of the nucleobase sequence of any of SEQ ID NO:         22-3669.     -   Embodiment 96. The oligomeric compound of any of embodiments         92-95, wherein the modified oligonucleotide has a nucleobase         sequence comprising at least 8, at least 9, at least 10, at         least 11, at least 12, at least 13, at least 14, at least 15, at         least 16, or at least 17 contiguous nucleobases of a sequence         selected from:         -   SEQ ID NOs: 196, 274, 352, 430, 508, 2578, 2655, 2732, 2809,             2886, 2963, 3121, 3122, 3190, 3191, 3192, 3262, 3330, 3331,             3332, 3401, 3402, 3575, 3577, 3620, 3624, 3638-3640,             3653-3655, 3662, 3665, 3669;         -   SEQ ID Nos: 42, 120, 198, 276, 509, 587, 2502, 2579, 2656,             2733, 2810, 2887, 2964, 3585, 3588-3590, 3615, 3618, 3622,             3657, 3660, 3661, 3663, 3664, 3666-3668;         -   SEQ ID Nos: 48, 126, 2044, 2121;         -   SEQ ID Nos: 128, 206, 284, 1045, 1122, 1199, and 1276; or         -   SEQ ID Nos: 2475, 2552, 2629, 2706, 2783, 3627-3630, 3644.     -   Embodiment 97. The oligomeric compound of any of embodiments         92-95, wherein the modified oligonucleotide has a nucleobase         sequence comprising at least 8, at least 9, at least 10, at         least 11, at least 12, at least 13, at least 14, at least 15, at         least 16, or 17 contiguous nucleobases of any of the nucleobase         sequences of SEQ ID NO: 3638.     -   Embodiment 98. The oligomeric compound of any of embodiments         92-95, wherein the modified oligonucleotide has a nucleobase         sequence comprising at least 8, at least 9, at least 10, at         least 11, at least 12, at least 13, at least 14, at least 15, at         least 16, at least 17, at least 18, at least 19, or 20         contiguous nucleobases of any of the nucleobase sequences of SEQ         ID NO: 126, 1045, 2552, 3190, or 3590.     -   Embodiment 99. The oligomeric compound of embodiment 97 or 98,         wherein the modified oligonucleotide consists of 17 to 30 linked         nucleosides and has a nucleobase sequence comprising the         nucleobase sequence of any of 126, 1045, 2552, 3190, 3590, or         3638.     -   Embodiment 100. The oligomeric compound of embodiment 99,         wherein the modified oligonucleotide has a nucleobase sequence         consisting of the nucleobase sequence of any one of 126, 1045,         2552, 3190, 3590, or 3638.     -   Embodiment 101. The oligomeric compound of any of embodiments         92-100, wherein the nucleobase sequence of the modified         oligonucleotide is at least 85%, at least 90%, at least 95%, or         100% complementary to an equal length portion of the ATXN1         nucleic acid, wherein the ATXN1 nucleic acid has the nucleobase         sequence of SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO:         4, SEQ ID NO: 5, or SEQ ID NO: 6.     -   Embodiment 102. The oligomeric compound of any of embodiments         87-101, wherein at least one nucleoside of the modified         oligonucleotide comprises a modified sugar moiety.     -   Embodiment 103. The oligomeric compound of embodiment 102,         wherein the modified sugar moiety comprises a bicyclic sugar         moiety.     -   Embodiment 104. The oligomeric compound of embodiment 103,         wherein the bicyclic sugar moiety comprises a 2′-4′ bridge         selected from —O—CH₂—; and —O—CH(CH₃)—.     -   Embodiment 105. The oligomeric compound of any of embodiments         102-104, wherein the modified nucleoside comprises a         non-bicyclic modified sugar moiety.     -   Embodiment 106. The oligomeric compound of embodiment 105,         wherein the non-bicyclic modified sugar moiety is a 2′-MOE sugar         moiety or 2′-OMe modified sugar moiety.     -   Embodiment 107. The oligomeric compound of any of embodiments         102-106, wherein at least one nucleoside of the modified         oligonucleotide comprises a sugar surrogate.     -   Embodiment 108. The oligomeric compound of embodiment 107,         wherein the sugar surrogate is selected from morpholino and PNA.     -   Embodiment 109. The oligomeric compound of any of embodiments         87-102 or 105-108, wherein the modified oligonucleotide does not         comprise a bicyclic sugar moiety.     -   Embodiment 110. The oligomeric compound of any of embodiments         87-109, wherein the modified oligonucleotide comprises at least         one modified internucleoside linkage.     -   Embodiment 111. The oligomeric compound of embodiment 110,         wherein at least one modified internucleoside linkage is a         phosphorothioate internucleoside linkage.     -   Embodiment 112. The oligomeric compound of embodiment 110 or         111, wherein each internucleoside linkage is a modified         internucleoside linkage.     -   Embodiment 113. The oligomeric compound of embodiment 112,         wherein each internucleoside linkage is a phosphorothioate         internucleoside linkage.     -   Embodiment 114. The oligomeric compound of any of embodiments         110-111, wherein at least one internucleoside linkage of the         modified oligonucleotide is a phosphodiester internucleoside         linkage.     -   Embodiment 115. The oligomeric compound of any of embodiments         87-109, wherein each internucleoside linkage of the modified         oligonucleotide is independently selected from a phosphodiester         or a phosphorothioate internucleoside linkage.     -   Embodiment 116. The oligomeric compound of any of embodiments         87-115, wherein at least 10, at least 11, at least 12, at least         13, at least 14, at least 15, at least 16, at least 17, or at         least 18 internucleoside linkages of the modified         oligonucleotide are phosphorothioate internucleoside linkages.     -   Embodiment 117. The oligomeric compound of embodiment 116,         wherein the modified oligonucleotide has an internucleoside         linkage motif selected from: sooosssssssssssooss,         sssosssssssssssosss, sssosssssssssoss, or sooooossssssssssoss;         wherein,         -   s=a phosphorothioate internucleoside linkage and o=a             phosphodiester internucleoside linkage.     -   Embodiment 118. The oligomeric compound of any of embodiments         87-117, wherein the modified oligonucleotide comprises a         modified nucleobase.     -   Embodiment 119. The oligomeric compound of embodiment 118,         wherein the modified nucleobase is a 5-methyl cytosine.     -   Embodiment 120. The oligomeric compound of any of embodiments         1-33, wherein the modified oligonucleotide comprises a deoxy         region consisting of 5-12 contiguous 2′-deoxynucleosides.     -   Embodiment 121. The oligomeric compound of embodiment 120,         wherein each nucleoside of the deoxy region is a         2′-β-D-deoxynucleoside.     -   Embodiment 122. The oligomeric compound of embodiment 120 or 121         wherein the deoxy region consists of 6, 7, 8, 9, 10, or 6-10         linked nucleosides.     -   Embodiment 123. The oligomeric compound of any of embodiments         120-122, wherein each nucleoside immediately adjacent to the         deoxy region comprises a modified sugar moiety.     -   Embodiment 124. The oligomeric compound of any of embodiments         120-122, wherein the deoxy region is flanked on the 5′-side by a         5′-region consisting of 1-6 linked 5′-region nucleosides and on         the 3′-side by a 3′external region consisting of 1-6 linked         3′-region nucleosides; wherein         -   the 3′-most nucleoside of the 5′-region comprises a modified             sugar moiety; and         -   the 5′-most nucleoside of the 3′-region comprises a modified             sugar moiety.     -   Embodiment 125. The oligomeric compound of embodiment 124,         wherein each nucleoside of the 3′-region comprises a modified         sugar moiety.     -   Embodiment 126. The oligomeric compound of embodiment 124 or         125, wherein each nucleoside of the 5′-region comprises a         modified sugar moiety.     -   Embodiment 127. The oligomeric compound of embodiment 120-126,         wherein the modified oligonucleotide has         -   a 5′-region consisting of 1-6 linked nucleosides;         -   a deoxy region consisting of 6-10 linked nucleosides; and         -   a 3′-region consisting of 1-6 linked nucleosides; wherein         -   each of the 5′-region nucleosides and each of the 3′-region             nucleosides comprises a modified sugar moiety.     -   Embodiment 128. The oligomeric compound of embodiment 127,         wherein the modified oligonucleotide has         -   a 5′-region consisting of 6 linked nucleosides;         -   a deoxy region consisting of 10 linked nucleosides; and         -   a 3′-region consisting of 4 linked nucleosides; wherein         -   each of the 5′-region nucleosides and each of the 3′-region             nucleosides is a 2′-MOE nucleoside, and         -   each of the deoxy region nucleosides is a             2′-β-D-deoxynucleoside.     -   Embodiment 129. The oligomeric compound of embodiment 127,         wherein the modified oligonucleotide has         -   a 5′-region consisting of 5 linked nucleosides;         -   a central region consisting of 10 linked nucleosides; and         -   a 3′-region consisting of 5 linked nucleosides; wherein         -   each of the 5′-region nucleosides and each of the 3′-region             nucleosides is a 2′-MOE nucleoside, and         -   each of the deoxy region nucleosides is a             2′-β-D-deoxynucleoside.     -   Embodiment 130. The oligomeric compound of embodiment 127,         wherein the modified oligonucleotide has         -   a 5′-region consisting of 5 linked nucleosides;         -   a deoxy region consisting of 8 linked nucleosides; and         -   a 3′-region consisting of 4 linked nucleosides; wherein         -   each of the 5′-region nucleosides and each of the 3′-region             nucleosides is a 2′-MOE nucleoside, and         -   each of the deoxy region nucleosides is a             2′-β-D-deoxynucleoside.     -   Embodiment 131. The oligomeric compound of embodiment 127,         wherein the modified oligonucleotide has         -   a 5′-region consisting of 5 linked nucleosides;         -   a deoxy region consisting of 8 linked nucleosides; and         -   a 3′-region consisting of 4 linked nucleosides; wherein         -   each of the 5′-region nucleosides is a 2′-MOE nucleoside,             each of the 3′-region nucleosides is selected from a 2′-MOE             nucleoside and a cEt nucleoside, and each of the deoxy             region nucleosides is a 2′-β-D-deoxynucleoside.     -   Embodiment 132. The oligomeric compound of any of embodiments         87-119, wherein the modified oligonucleotide has         -   a 5′ region consisting of 3-7 linked nucleosides;         -   a deoxy region consisting of 6-8 linked nucleosides; and         -   a 3′ region consisting of 3-6 linked nucleosides; wherein         -   each of the 3′ region nucleosides is selected from a 2′-MOE             nucleoside and a cEt nucleoside, and the 5′ region has the             following formula:             (Nk)n(Nd)(Nx)         -   wherein each Nk is a bicyclic nucleoside, Nx is a 2′-OMe             nucleoside and Nd is a 2′-β-D-deoxynucleoside;         -   and n is from 1-5.     -   Embodiment 133. The oligomeric compound of any of embodiments         87-119, wherein the modified oligonucleotide has         -   a 5′ region consisting of 7 linked nucleosides;         -   a deoxy region consisting of 6 linked nucleosides; and         -   a 3′ region consisting of 4 linked nucleosides; wherein         -   each of the 3′ region nucleosides is selected from a 2′-MOE             nucleoside and a cEt nucleoside, and the 5′ region has the             following formula:             (Nk)n(Nd)(Nx)         -   wherein each Nk is a bicyclic nucleoside, Nx is a 2′-OMe             nucleoside and Nd is a 2′-β-D-deoxynucleoside;         -   and n is from 5.     -   Embodiment 134. The oligomeric compound of any of embodiments         87-133, wherein the modified oligonucleotide consists of 12-30,         12-22, 12-20, 14-18, 16-18, 14-20, 15-17, 15-25, 16-20, or 17-20         linked nucleosides.     -   Embodiment 135. The oligomeric compound of any of embodiments         87-132, wherein the modified oligonucleotide consists of 18-22         or 18-20 linked nucleosides.     -   Embodiment 136. The oligomeric compound of any of embodiments         87-133, wherein the modified oligonucleotide consists of 17         linked nucleosides.     -   Embodiment 137. The oligomeric compound of any of embodiments         87-132, wherein the modified oligonucleotide consists of 20         linked nucleosides.     -   Embodiment 138. A compound comprising a modified oligonucleotide         according to the following chemical notation:         -   Ges ^(m)Ceo Aeo ^(m)Ceo Ges Gds Tds Ads Tds Tds Ads Gds Tds             Gds Tds ^(m)Ceo Teo Tes ^(m)Ces Ae (SEQ ID NO: 126),             wherein,         -   A=an adenine nucleobase,         -   ^(m)C=a 5-methyl cytosine nucleobase,         -   G=a guanine nucleobase,         -   T=a thymine nucleobase,         -   e=a 2′-MOE sugar moiety,         -   d=a 2′-β-D deoxyribosyl sugar moiety,         -   s=a phosphorothioate internucleoside linkage, and         -   o=a phosphodiester internucleoside linkage.     -   Embodiment 139. A compound comprising a modified oligonucleotide         according to the following chemical notation:         -   Ges ^(m)Ceo Teo Teo ^(m)Ces Tds ^(m)Cds Ads Ads Ads Tds             ^(m)Cds Ads Gds Gds Teo Geo Tes Aes mCe (SEQ ID NO: 1045),             wherein,         -   A=an adenine nucleobase,         -   ^(m)C=a 5-methyl cytosine nucleobase,         -   G=a guanine nucleobase,         -   T=a thymine nucleobase,         -   e=a 2′-MOE sugar moiety,         -   d=a 2′-β-D deoxyribosyl sugar moiety,         -   s=a phosphorothioate internucleoside linkage, and         -   o=a phosphodiester internucleoside linkage.     -   Embodiment 140. A compound comprising a modified oligonucleotide         according to the following chemical notation:         -   Ges ^(m)Ceo ^(m)Ceo Teo Tes Tds Ads Tds Ads Ads ^(m)Cds Tds             Tds Tds Tds ^(m)Ceo Teo Tes Tes ^(m)Ce (SEQ ID NO: 2552),             wherein,         -   A=an adenine nucleobase,         -   ^(m)C=a 5-methyl cytosine nucleobase,         -   G=a guanine nucleobase,         -   T=a thymine nucleobase,         -   e=a 2′-MOE sugar moiety,         -   d=a 2′-β-D deoxyribosyl sugar moiety,         -   s=a phosphorothioate internucleoside linkage, and         -   o=a phosphodiester internucleoside linkage.     -   Embodiment 141. A compound comprising a modified oligonucleotide         according to the following chemical notation:         -   Tes Teo ^(m)Ceo Aeo Ges Tds Tds Tds Ads Gds Tds Tds Gds             ^(m)Cds Ads Geo ^(m)Ceo ^(m)Ces Aes Te (SEQ ID NO: 3190),             wherein,         -   A=an adenine nucleobase,         -   ^(m)C=a 5-methyl cytosine nucleobase,         -   G=a guanine nucleobase,         -   T=a thymine nucleobase,         -   e=a 2′-MOE sugar moiety,         -   d=a 2′-β-D deoxyribosyl sugar moiety,         -   s=a phosphorothioate internucleoside linkage, and         -   o=a phosphodiester internucleoside linkage.     -   Embodiment 142. A compound comprising a modified oligonucleotide         according to the following chemical notation:         -   ^(m)Ces ^(m)Ceo ^(m)Ceo Geo Tes Ads Tds Tds ^(m)Cds ^(m)Cds             Tds ^(m)Cds Tds Tds Ads ^(m)Ceo ^(m)Ceo Aes Tes ^(m)Ce (SEQ             ID NO: 3590), wherein,         -   A=an adenine nucleobase,         -   ^(m)C=a 5-methyl cytosine nucleobase,         -   G=a guanine nucleobase,         -   T=a thymine nucleobase,         -   e=a 2′-MOE sugar moiety,         -   d=a 2′-β-D deoxyribosyl sugar moiety,         -   s=a phosphorothioate internucleoside linkage, and         -   o=a phosphodiester internucleoside linkage.     -   Embodiment 143. A compound comprising a modified oligonucleotide         according to the following chemical notation:         -   Tes ^(m)Ces Aes Geo Tes Tds Tds Ads Gds Tds Tds Gds ^(m)Cds             Aeo Ges ^(m)Ces ^(m)Ce (SEQ ID NO: 3638),         -   wherein,         -   A=an adenine nucleobase,         -   ^(m)C=a 5-methyl cytosine nucleobase,         -   G=a guanine nucleobase,         -   T=a thymine nucleobase,         -   e=a 2′-MOE sugar moiety,         -   d=a 2′-β-D deoxyribosyl sugar moiety,         -   s=a phosphorothioate internucleoside linkage, and         -   o=a phosphodiester internucleoside linkage.     -   Embodiment 144. The oligomeric compound of any of embodiments         87-143, consisting of the modified oligonucleotide.     -   Embodiment 145. The oligomeric compound of any of embodiments         87-144, comprising a conjugate group comprising a conjugate         moiety and a conjugate linker.     -   Embodiment 146. The oligomeric compound of embodiment 145,         wherein the conjugate linker consists of a single bond.     -   Embodiment 147. The oligomeric compound of embodiment 145,         wherein the conjugate linker is cleavable.     -   Embodiment 148. The oligomeric compound of embodiment 145,         wherein the conjugate linker comprises 1-3 linker nucleosides.     -   Embodiment 149. The oligomeric compound of any of embodiments         145-148, wherein the conjugate linker does not comprise any         linker nucleosides.     -   Embodiment 150. The oligomeric compound of any of embodiments         145-148, wherein the conjugate group is attached to the modified         oligonucleotide at the 5′-end of the modified oligonucleotide.     -   Embodiment 151. The oligomeric compound of any of embodiments         145-148, wherein the conjugate group is attached to the modified         oligonucleotide at the 3′-end of the modified oligonucleotide.     -   Embodiment 152. The oligomeric compound of any of embodiments         87-143 or 146-148, comprising a terminal group.     -   Embodiment 153. The oligomeric compound of embodiment 152,         wherein the terminal group is an abasic sugar moiety.     -   Embodiment 154. The oligomeric compound of any of embodiments         87-153 wherein the oligomeric compound is a singled-stranded         oligomeric compound.     -   Embodiment 155. A modified oligonucleotide according to the         following chemical structure:

or a salt thereof.

-   -   Embodiment 156. A modified oligonucleotide according to the         following chemical structure:

or a salt thereof.

-   -   Embodiment 157. A modified oligonucleotide according to the         following chemical structure:

or a salt thereof.

-   -   Embodiment 158. A modified oligonucleotide according to the         following chemical structure:

or a salt thereof.

-   -   Embodiment 159. A modified oligonucleotide according to the         following chemical structure:

or a salt thereof.

-   -   Embodiment 160. A modified oligonucleotide according to the         following chemical structure:

-   -   -   or a salt thereof.

    -   Embodiment 161. The modified oligonucleotide of any of         embodiments 155-160, which is the sodium salt or the potassium         salt.

    -   Embodiment 162. A modified oligonucleotide according to the         following chemical structure:

-   -   Embodiment 163. A modified oligonucleotide according to the         following chemical structure:

-   -   Embodiment 164. A modified oligonucleotide according to the         following chemical structure:

-   -   Embodiment 165. A modified oligonucleotide according to the         following chemical structure:

-   -   Embodiment 166. A modified oligonucleotide according to the         following chemical structure:

-   -   Embodiment 167. A modified oligonucleotide according to the         following chemical structure:

-   -   Embodiment 168. A chirally enriched population of oligomeric         compounds of any of embodiments 87-154 or modified         oligonucleotide of embodiments 155-167, wherein the population         is enriched for modified oligonucleotides comprising at least         one particular phosphorothioate internucleoside linkage having a         particular stereochemical configuration.     -   Embodiment 169. The chirally enriched population of embodiment         168, wherein the population is enriched for modified         oligonucleotides comprising at least one particular         phosphorothioate internucleoside linkage having the (Sp) or (Rp)         configuration.     -   Embodiment 170. The chirally enriched population of embodiment         169, wherein the population is enriched for modified         oligonucleotides having a particular, independently selected         stereochemical configuration at each phosphorothioate         internucleoside linkage.     -   Embodiment 171. The chirally enriched population of embodiment         170, wherein the population is enriched for modified         oligonucleotides having the (Rp) configuration at one particular         phosphorothioate internucleoside linkage and the (Sp)         configuration at each of the remaining phosphorothioate         internucleoside linkages.     -   Embodiment 172. The chirally enriched population of embodiment         171, wherein the population is enriched for modified         oligonucleotides having at least 3 contiguous phosphorothioate         internucleoside linkages in the Sp, Sp, and Rp configurations,         in the 5′ to 3′ direction.     -   Embodiment 173. A population of oligomeric compounds comprising         modified oligonucleotides of any of embodiments 87-154, or a         population of modified oligonucleotides of embodiments 155-167,         wherein all of the phosphorothioate internucleoside linkages of         the modified oligonucleotide are stereorandom.     -   Embodiment 174. An oligomeric duplex, comprising a first         oligomeric compound and a second oligomeric compound comprising         a second modified oligonucleotide, wherein the first oligomeric         compound is an oligomeric compound of any of embodiments 87-154.     -   Embodiment 175. The oligomeric duplex of embodiment 174, wherein         the second oligomeric compound comprises a second modified         oligonucleotide consisting of 12 to 30 linked nucleosides, and         wherein the nucleobase sequence of the second modified         oligonucleotide comprises a complementary region of at least 8         nucleobases that is at least 90% complementary to an equal         length portion of the first modified oligonucleotide.     -   Embodiment 176. The oligomeric duplex of embodiment 174 or 175,         wherein the modified oligonucleotide of the first oligomeric         compound comprises a 5′-stabilized phosphate group.     -   Embodiment 177. The oligomeric duplex of embodiment 176, wherein         the stabilized phosphate group comprises a cyclopropyl         phosphonate or a vinyl phosphonate.     -   Embodiment 178. The oligomeric duplex of any of embodiments         174-177, wherein the modified oligonucleotide of the first         oligomeric compound comprises a glycol nucleic acid (GNA) sugar         surrogate.     -   Embodiment 179. The oligomeric duplex of any of embodiments         174-178, wherein the modified oligonucleotide of the first         oligomeric compound comprises a 2′-NMA sugar moiety.     -   Embodiment 180. The oligomeric duplex of any of embodiments         174-179, wherein at least one nucleoside of the second modified         oligonucleotide comprises a modified sugar moiety.     -   Embodiment 181. The oligomeric duplex of embodiment 180, wherein         the modified sugar moiety of the second modified oligonucleotide         comprises a bicyclic sugar moiety.     -   Embodiment 182. The oligomeric duplex of embodiment 181, wherein         the bicyclic sugar moiety of the second modified oligonucleotide         comprises a 2′-4′ bridge selected from —O—CH_(r)—; and         —O—CH(CH₃)—.     -   Embodiment 183. The oligomeric duplex of embodiment 182, wherein         the modified sugar moiety of the second modified oligonucleotide         comprises a non-bicyclic modified sugar moiety.     -   Embodiment 184. The oligomeric duplex of embodiment 183, wherein         the non-bicyclic modified sugar moiety of the second modified         oligonucleotide is a 2′-MOE sugar moiety, a 2′-F sugar moiety,         or 2′-OMe sugar moiety.     -   Embodiment 185. The oligomeric duplex of any of embodiments         174-184, wherein at least one nucleoside of the second modified         oligonucleotide comprises a sugar surrogate.     -   Embodiment 186. The oligomeric duplex of any of embodiments         174-185, wherein at least one internucleoside linkage of the         second modified oligonucleotide is a modified internucleoside         linkage.     -   Embodiment 187. The oligomeric duplex of embodiment 186, wherein         at least one modified internucleoside linkage of the second         modified oligonucleotide is a phosphorothioate internucleoside         linkage.     -   Embodiment 188. The oligomeric duplex of any of embodiments         174-187, wherein at least one internucleoside linkage of the         second modified oligonucleotide is a phosphodiester         internucleoside linkage.     -   Embodiment 189. The oligomeric duplex of any of embodiments         174-188, wherein each internucleoside linkage of the second         modified oligonucleotide is independently selected from a         phosphodiester or a phosphorothioate internucleoside linkage.     -   Embodiment 190. The oligomeric duplex of any of embodiments         174-189, wherein each internucleoside linkage of the second         modified oligonucleotide is independently selected from a         phosphodiester internucleoside linkage, a phosphorothioate         internucleoside linkage, or a mesyl phosphoramidate         internucleoside linkage.     -   Embodiment 191. The oligomeric duplex of any of embodiments         174-190, wherein the second modified oligonucleotide comprises         at least one modified nucleobase.     -   Embodiment 192. The oligomeric duplex of embodiment 191, wherein         the modified nucleobase of the second modified oligonucleotide         is 5-methylcytosine.     -   Embodiment 193. The oligomeric duplex of any of embodiments         174-192, wherein the second modified oligonucleotide comprises a         conjugate group.     -   Embodiment 194. The oligomeric duplex of embodiment 193, wherein         the conjugate group comprises a conjugate linker and a conjugate         moiety.     -   Embodiment 195. The oligomeric duplex of embodiment 193 or 194,         wherein the conjugate group is attached to the second modified         oligonucleotide at the 5′-end of the second modified         oligonucleotide.     -   Embodiment 196. The oligomeric duplex of embodiment 193 or 194,         wherein the conjugate group is attached to the second modified         oligonucleotide at the 3′-end of the modified oligonucleotide.     -   Embodiment 197. The oligomeric duplex of any of embodiments         193-196, wherein the second modified oligonucleotide comprises a         terminal group.     -   Embodiment 198. The oligomeric duplex of embodiment 197, wherein         the terminal group is an abasic sugar moiety.     -   Embodiment 199. The oligomeric duplex of any of embodiments         174-198, wherein the second modified oligonucleotide consists of         10 to 25, 10 to 30, 10 to 50, 12 to 20, 12 to 25, 12 to 30, 12         to 50, 13 to 20, 13 to 25, 13 to 30, 13 to 50, 14 to 20, 14 to         25, 14 to 30, 14 to 50, 15 to 20, 15 to 25, 15 to 30, 15 to 50,         16 to 18, 16 to 20, 16 to 25, 16 to 30, 16 to 50, 17 to 20, 17         to 25, 17 to 30, 17 to 50, 18 to 20, 18 to 25, 18 to 30, 18 to         50, 19 to 20, 19 to 25, 19 to 30, 19 to 50, 20 to 25, 20 to 30,         20 to 50, 21 to 25, 21 to 30, 21 to 50, 22 to 25, 22 to 30, 22         to 50, 23 to 25, 23 to 30, or 23 to 50 linked nucleosides.     -   Embodiment 200. An antisense agent comprising an antisense         compound, wherein the antisense compound is the oligomeric         compound of any of embodiments 87-154 or the modified         oligonucleotide of any of embodiments 155-167.     -   Embodiment 201. The antisense agent of embodiment 200, wherein         the antisense agent is the oligomeric duplex of any of         embodiments 174-199.     -   Embodiment 202. The antisense agent of embodiment 200 or 201,         wherein the antisense agent is an RNase H agent capable of         reducing the amount of ATXN1 nucleic acid through the activation         of RNase H.     -   Embodiment 203. The antisense agent of any of embodiments         200-202, wherein the conjugate group comprises a cell-targeting         moiety.     -   Embodiment 204. A pharmaceutical composition comprising an         oligomeric compound of any of embodiments 87-154, the modified         oligonucleotide of any of embodiments 155-167, the population of         any of embodiments 168-173, an oligomeric duplex of any of         embodiments 174-199, or an antisense agent of any of embodiments         200-203, and a pharmaceutically acceptable carrier or diluent.     -   Embodiment 205. The pharmaceutical composition of embodiment         204, wherein the pharmaceutically acceptable diluent is water,         phosphate-buffered saline, or artificial cerebral spinal fluid.     -   Embodiment 206. The pharmaceutical composition of embodiment         205, wherein the pharmaceutical composition consists essentially         of the modified oligonucleotide and artificial cerebral spinal         fluid.     -   Embodiment 207. A method comprising administering to a subject         the oligomeric compound of any of embodiments 87-154, the         modified oligonucleotide of any of embodiments 155-167, the         population of any of embodiments 168-173, the oligomeric duplex         of any of embodiments 174-199, the antisense agent of any of         embodiments 200-203, or the pharmaceutical composition of any of         embodiments 204-206.     -   Embodiment 208. A method of treating a disease associated with         ATXN1 comprising administering to a subject having a disease         associated with ATXN1 a therapeutically effective amount of the         oligomeric compound of any of embodiments 87-154, the modified         oligonucleotide of any of embodiments 155-167, the population of         any of embodiments 168-173, the oligomeric duplex of any of         embodiments 174-199, the antisense agent of any of embodiments         200-203, or the pharmaceutical composition of any of embodiments         204-206; thereby treating the disease associated with ATXN1.     -   Embodiment 209. The method of embodiment 208, wherein the         ATXN1-associated disease is Spinocerebellar ataxia type 1.     -   Embodiment 210. The method of any of embodiments 208-209,         wherein at least one symptom or hallmark of the ATXN1-associated         disease is ameliorated.     -   Embodiment 211. The method of embodiment 210, wherein the         symptom or hallmark is gait or limb ataxia, cognitive         impairments, difficulty with speaking or swallowing, atrophy of         the cerebellum and/or brainstem in magnetic resonance imaging         (MRI), neurochemical abnormalities in the cerebellum and/or         brainstem detected via magnetic resonance spectroscopy (MRS), or         death within 10-15 years of symptom onset.     -   Embodiment 212. The method of any of embodiments 208-211,         wherein ATXN1 levels in the subject are reduced.     -   Embodiment 213. A method of reducing expression of ATXN1 in a         cell comprising contacting the cell with the oligomeric compound         of any of embodiments 87-154, the modified oligonucleotide of         any of embodiments 155-167, the population of any of embodiments         168-173, the oligomeric duplex of any of embodiments 174-199,         the antisense agent of any of embodiments 200-203, or the         pharmaceutical composition of any of embodiments 204-206.     -   Embodiment 214. The method of embodiment 213, wherein the cell         is a CNS cell.     -   Embodiment 215. Use of the oligomeric compound of any of         embodiments 87-154, the modified oligonucleotide of any of         embodiments 155-167, the population of any of embodiments         168-173, the oligomeric duplex of any of embodiments 174-199,         the antisense agent of any of embodiments 200-203, or the         pharmaceutical composition of any of embodiments 204-206 for         treating a disease associated with ATXN1.     -   Embodiment 216. Use of the oligomeric compound of any of         embodiments 87-154, the modified oligonucleotide of any of         embodiments 155-167, the population of any of embodiments         168-173, the oligomeric duplex of any of embodiments 174-199,         the antisense agent of any of embodiments 200-203, or the         pharmaceutical composition of any of embodiments 204-206 in the         manufacture of a medicament for treating a disease associated         with ATXN1.     -   Embodiment 217. The use of embodiment 215 or 216, wherein the         disease associated with ATXN1 is Spinocerebellar ataxia type 1.         I. Certain Oligonucleotides

In certain embodiments, provided herein are oligomeric compounds comprising oligonucleotides, which consist of linked nucleosides. Oligonucleotides may be unmodified oligonucleotides (RNA or DNA) or may be modified oligonucleotides. Modified oligonucleotides comprise at least one modification relative to unmodified RNA or DNA. That is, modified oligonucleotides comprise at least one modified nucleoside (comprising a modified sugar moiety and/or a modified nucleobase) and/or at least one modified internucleoside linkage.

A. Certain Modified Nucleosides

Modified nucleosides comprise a modified sugar moiety or a modified nucleobase or both a modified sugar moiety and a modified nucleobase.

1. Certain Sugar Moieties

In certain embodiments, modified sugar moieties are non-bicyclic modified sugar moieties. In certain embodiments, modified sugar moieties are bicyclic or tricyclic sugar moieties. In certain embodiments, modified sugar moieties are sugar surrogates. Such sugar surrogates may comprise one or more substitutions corresponding to those of other types of modified sugar moieties.

In certain embodiments, modified sugar moieties are non-bicyclic modified sugar moieties comprising a furanosyl ring with one or more substituent groups none of which bridges two atoms of the furanosyl ring to form a bicyclic structure. Such non bridging substituents may be at any position of the furanosyl, including but not limited to substituents at the 2′, 4′, and/or 5′ positions. In certain embodiments one or more non-bridging substituent of non-bicyclic modified sugar moieties is branched. Examples of 2′-substituent groups suitable for non-bicyclic modified sugar moieties include but are not limited to: 2′-F, 2′-OCH₃ (“OMe” or “O-methyl”), and 2′-O(CH₂)₂OCH₃ (“MOE” or “O-methoxyethyl”). In certain embodiments, 2′-substituent groups are selected from among: halo, allyl, amino, azido, SH, CN, OCN, CF₃, OCF₃, O—C₁-C₁₀ alkoxy, O—C₁-C₁₀ substituted alkoxy, O—C₁-C₁₀ alkyl, O—C₁-C₁₀ substituted alkyl, S-alkyl, N(R_(m))-alkyl, O-alkenyl, S-alkenyl, N(R_(m))-alkenyl, O-alkynyl, S-alkynyl, N(R_(m))-alkynyl, O-alkylenyl-O-alkyl, alkynyl, alkaryl, aralkyl, O-alkaryl, O-aralkyl, O(CH₂)₂SCH₃, O(CH₂)₂ON(R_(m))(R_(n)) or OCH₂C(═O)—N(R_(m))(R_(n)), where each R_(m) and R_(n) is, independently, H, an amino protecting group, or substituted or unsubstituted C₁-C₁₀ alkyl, and the 2′-substituent groups described in Cook et al., U.S. Pat. No. 6,531,584; Cook et al., U.S. Pat. No. 5,859,221; and Cook et al., U.S. Pat. No. 6,005,087. Certain embodiments of these 2′-substituent groups can be further substituted with one or more substituent groups independently selected from among: hydroxyl, amino, alkoxy, carboxy, benzyl, phenyl, nitro (NO₂), thiol, thioalkoxy, thioalkyl, halogen, alkyl, aryl, alkenyl and alkynyl. Examples of 4′-substituent groups suitable for non-bicyclic modified sugar moieties include but are not limited to alkoxy (e.g., methoxy), alkyl, and those described in Manoharan et al., WO 2015/106128. Examples of 5′-substituent groups suitable for non-bicyclic modified sugar moieties include but are not limited to: 5-methyl (R or S), 5′-vinyl, and 5′-methoxy. In certain embodiments, non-bicyclic modified sugar moieties comprise more than one non-bridging sugar substituent, for example, 2′-F-5′-methyl sugar moieties and the modified sugar moieties and modified nucleosides described in Migawa et al., WO 2008/101157 and Rajeev et al., US2013/0203836.

In certain embodiments, a 2′-substituted non-bicyclic modified nucleoside comprises a sugar moiety comprising a non-bridging 2′-substituent group selected from: F, NH₂, N₃, OCF₃, OCH₃, O(CH₂)₃NH₂, CH₂CH═CH₂, OCH₂CH═CH₂, OCH₂CH₂OCH₃, O(CH₂)₂SCH₃, O(CH₂)₂ON(R_(m))(R_(n)), O(CH₂)₂O(CH₂)₂N(CH₃)₂, and N-substituted acetamide (OCH₂C(═O)—N(R_(m))(R_(n))), where each R_(m) and R_(n) is, independently, H, an amino protecting group, or substituted or unsubstituted C₁-C₁₀ alkyl.

In certain embodiments, a 2′-substituted nucleoside non-bicyclic modified nucleoside comprises a sugar moiety comprising a non-bridging 2′-substituent group selected from: F, OCF₃, OCH₃, OCH₂CH₂OCH₃, O(CH₂)₂SCH₃, O(CH₂)₂ON(CH₃)₂, O(CH₂)₂O(CH₂)₂N(CH₃)₂, and OCH₂C(═O)—N(H)CH₃ (“NMA”).

In certain embodiments, a 2′-substituted nucleoside comprises a sugar moiety comprising a non-bridging 2′-substituent group selected from: F, OCH₃, and OCH₂CH₂OCH₃.

In certain embodiments, modified furanosyl sugar moieties and nucleosides incorporating such modified furanosyl sugar moieties are further defined by isomeric configuration. For example, a 2′-deoxyfuranosyl sugar moiety may be in seven isomeric configurations other than the naturally occurring β-D-deoxyribosyl configuration. Such modified sugar moieties are described in, e.g., WO 2019/157531, incorporated by reference herein. A 2′-modified sugar moiety has an additional stereocenter at the 2′-position relative to a 2′-deoxyfuranosyl sugar moiety; therefore, such sugar moieties have a total of sixteen possible isomeric configurations. 2′-modified sugar moieties described herein are in the β-D-ribosyl isomeric configuration unless otherwise specified.

Certain modified sugar moieties comprise a substituent that bridges two atoms of the furanosyl ring to form a second ring, resulting in a bicyclic sugar moiety. In certain such embodiments, the bicyclic sugar moiety comprises a bridge between the 4′ and the 2′ furanose ring atoms. Examples of such 4′ to 2′ bridging sugar substituents include but are not limited to: 4′-CH₂-2′, 4′-(CH₂)₂-2′, 4′-(CH₂)₃-2′, 4′-CH₂—O-2′ (“LNA”), 4′-CH₂—S-2′, 4′-(CH₂)₂-O-2′ (“ENA”), 4′-CH(CH₃)—O-2′ (referred to as “constrained ethyl” or “cEt”), 4′-CH₂—O—CH₂-2′, 4′-CH₂—N(R)-2′, 4′-CH(CH₂OCH₃)—O-2′ (“constrained MOE” or “cMOE”) and analogs thereof (see, e.g., Seth et al., U.S. Pat. No. 7,399,845, Bhat et al., U.S. Pat. No. 7,569,686, Swayze et al., U.S. Pat. No. 7,741,457, and Swayze et al., U.S. Pat. No. 8,022,193), 4′-C(CH₃)(CH₃)—O-2′ and analogs thereof (see, e.g., Seth et al., U.S. Pat. No. 8,278,283), 4′-CH₂—N(OCH₃)-2′ and analogs thereof (see, e.g., Prakash et al., U.S. Pat. No. 8,278,425), 4′-CH₂—O—N(CH₃)-2′ (see, e.g., Allerson et al., U.S. Pat. No. 7,696,345 and Allerson et al., U.S. Pat. No. 8,124,745), 4′-CH₂—C(H)(CH₃)-2′ (see, e.g., Zhou, et al., J. Org. Chem., 2009, 74, 118-134), 4′-CH₂—C(═CH₂)-2′ and analogs thereof (see e.g., Seth et al., U.S. Pat. No. 8,278,426), 4′-C(R_(a)R_(b))—N(R)—O-2′, 4′-C(R_(a)R_(b))—O—N(R)-2′, 4′-CH₂—O—N(R)-2′, and 4′-CH₂—N(R)—O- 2′, wherein each R, R_(a), and R_(b) is, independently, H, a protecting group, or C₁-C₁₂ alkyl (see, e.g. Imanishi et al., U.S. Pat. No. 7,427,672).

In certain embodiments, such 4′ to 2′ bridges independently comprise from 1 to 4 linked groups independently selected from: —[C(R_(a))(R_(b))]_(n)—, —[C(R_(a))(R_(b))]_(n)—O—, —C(R_(a))═C(R_(b))—, —C(R_(a))═N—, —C(═NR_(a))—, —C(═O)—, —C(═S)—, —O—, —Si(R_(a))₂-, —S(═O)_(x)—, and —N(R_(a))—;

wherein:

x is 0, 1, or 2;

n is 1, 2, 3, or 4;

each R_(a) and R_(b) is, independently, H, a protecting group, hydroxyl, C₁-C₁₂ alkyl, substituted C₁-C₁₂ alkyl, C₂-C₁₂ alkenyl, substituted C₂-C₁₂ alkenyl, C₂-C₁₂ alkynyl, substituted C₂-C₁₂ alkynyl, C₅-C₂₀ aryl, substituted C₅-C₂₀ aryl, heterocycle radical, substituted heterocycle radical, heteroaryl, substituted heteroaryl, C₅-C₇ alicyclic radical, substituted C₅-C₇ alicyclic radical, halogen, OJ₁, NJ₁J₂, SJ₁, N₃, COOJ₁, acyl (C(═O)—H), substituted acyl, CN, sulfonyl (S(═O)₂-J₁), or sulfoxyl (S(═O)-J₁); and

each J₁ and J₂ is, independently, H, C₁-C₁₂ alkyl, substituted C₁-C₁₂ alkyl, C₂-C₁₂ alkenyl, substituted C₂-C₁₂ alkenyl, C₂-C₁₂ alkynyl, substituted C₂-C₁₂ alkynyl, C₅-C₂₀ aryl, substituted C₅-C₂₀ aryl, acyl (C(═O)—H), substituted acyl, a heterocycle radical, a substituted heterocycle radical, C₁-C₁₂ aminoalkyl, substituted C₁-C₁₂ aminoalkyl, or a protecting group.

Additional bicyclic sugar moieties are known in the art, see, for example: Freier et al., Nucleic Acids Research, 1997, 25(22), 4429-4443, Albaek et al., J. Org. Chem., 2006, 71, 7731-7740, Singh et al., Chem. Commun., 1998, 4, 455-456; Koshkin et al., Tetrahedron, 1998, 54, 3607-3630; Kumar et al., Bioorg. Med. Chem. Lett., 1998, 8, 2219-2222; Singh et al., J. Org. Chem., 1998, 63, 10035-10039; Srivastava et al., J. Am. Chem. Soc., 2007, 129, 8362-8379; Wengel et al., U.S. Pat. No. 7,053,207; Imanishi et al., U.S. Pat. No. 6,268,490; Imanishi et al. U.S. Pat. No. 6,770,748; Imanishi et al., U.S. RE44,779; Wengel et al., U.S. Pat. No. 6,794,499; Wengel et al., U.S. Pat. No. 6,670,461; Wengel et al., U.S. Pat. No. 7,034,133; Wengel et al., U.S. Pat. No. 8,080,644; Wengel et al., U.S. Pat. No. 8,034,909; Wengel et al., U.S. Pat. No. 8,153,365; Wengel et al., U.S. Pat. No. 7,572,582; Ramasamy et al., U.S. Pat. No. 6,525,191; Torsten et al., WO 2004/106356; Wengel et al., WO 1999/014226; Seth et al., WO 2007/134181; Seth et al., U.S. Pat. No. 7,547,684; Seth et al., U.S. Pat. No. 7,666,854; Seth et al., U.S. Pat. No. 8,088,746; Seth et al., U.S. Pat. No. 7,750,131; Seth et al., U.S. Pat. No. 8,030,467; Seth et al., U.S. Pat. No. 8,268,980; Seth et al., U.S. Pat. No. 8,546,556; Seth et al., U.S. Pat. No. 8,530,640; Migawa et al., U.S. Pat. No. 9,012,421; Seth et al., U.S. Pat. No. 8,501,805; and U.S. Patent Publication Nos. Allerson et al., US2008/0039618 and Migawa et al., US2015/0191727.

In certain embodiments, bicyclic sugar moieties and nucleosides incorporating such bicyclic sugar moieties are further defined by isomeric configuration. For example, an LNA nucleoside (described herein) may be in the α-L configuration or in the β-D configuration.

α-L-methyleneoxy (4′-CH₂—O-2′) or α-L-LNA bicyclic nucleosides have been incorporated into oligonucleotides that showed antisense activity (Frieden et al., Nucleic Acids Research, 2003, 21, 6365-6372). Herein, general descriptions of bicyclic nucleosides include both isomeric configurations. When the positions of specific bicyclic nucleosides (e.g., LNA or cEt) are identified in exemplified embodiments herein, they are in the β-D configuration, unless otherwise specified.

In certain embodiments, modified sugar moieties comprise one or more non-bridging sugar substituent and one or more bridging sugar substituent (e.g., 5′-substituted and 4′-2′ bridged sugars).

In certain embodiments, modified sugar moieties are sugar surrogates. In certain such embodiments, the oxygen atom of the sugar moiety is replaced, e.g., with a sulfur, carbon or nitrogen atom. In certain such embodiments, such modified sugar moieties also comprise bridging and/or non-bridging substituents as described herein. For example, certain sugar surrogates comprise a 4′-sulfur atom and a substitution at the 2′-position (see, e.g., Bhat et al., U.S. Pat. No. 7,875,733 and Bhat et al., U.S. Pat. No. 7,939,677) and/or the 5′ position.

In certain embodiments, sugar surrogates comprise rings having other than 5 atoms. For example, in certain embodiments, a sugar surrogate comprises a six-membered tetrahydropyran (“THP”). Such tetrahydropyrans may be further modified or substituted. Nucleosides comprising such modified tetrahydropyrans include but are not limited to hexitol nucleic acid (“HNA”), anitol nucleic acid (“ANA”), manitol nucleic acid (“NINA”) (see, e.g., Leumann, C J. Bioorg. & Med. Chem. 2002, 10, 841-854), fluoro HNA:

(“F-HNA”, see e.g. Swayze et al., U.S. Pat. No. 8,088,904; Swayze et al., U.S. Pat. No. 8,440,803; Swayze et al., U.S. Pat. No. 8,796,437; and Swayze et al., U.S. Pat. No. 9,005,906; F-HNA can also be referred to as a F-THP or 3′-fluoro tetrahydropyran), and nucleosides comprising additional modified THP compounds having the formula:

wherein, independently, for each of the modified THP nucleosides:

Bx is a nucleobase moiety;

T₃ and T₄ are each, independently, an internucleoside linking group linking the modified THP nucleoside to the remainder of an oligonucleotide or one of T₃ and T₄ is an internucleoside linking group linking the modified THP nucleoside to the remainder of an oligonucleotide and the other of T₃ and T₄ is H, a hydroxyl protecting group, a linked conjugate group, or a 5′ or 3′-terminal group;

q₁, q₂, q₃, q₄, q₅, q₆ and q are each, independently, H, C₁-C₆ alkyl, substituted C₁-C₆ alkyl, C₂-C₆ alkenyl, substituted C₂-C₆ alkenyl, C₂-C₆ alkynyl, or substituted C₂-C₆ alkynyl; and

each of R₁ and R₂ is independently selected from among: hydrogen, halogen, substituted or unsubstituted alkoxy, NJ₁J₂, SJ₁, N₃, OC(═X)J₁, OC(═X)NJ₁J₂, NJ₃C(═X)NJ₁J₂, and CN, wherein X is O, S or NJ₁, and each J₁, J₂, and J₃ is, independently, H or C₁-C₆ alkyl.

In certain embodiments, modified THP nucleosides are provided wherein q₁, q₂, q₃, q₄, q₅, q₆ and q₇ are each H. In certain embodiments, at least one of q₁, q₂, q₃, q₄, q₅, q₆ and q₇ is other than H. In certain embodiments, at least one of q₁, q₂, q₃, q₄, q₅, q₆ and q₇ is methyl. In certain embodiments, modified THP nucleosides are provided wherein one of R₁ and R₂ is F. In certain embodiments, R₁ is F and R₂ is H, in certain embodiments, R₁ is methoxy and R₂ is H, and in certain embodiments, R₁ is methoxyethoxy and R₂ is H.

In certain embodiments, sugar surrogates comprise rings having more than 5 atoms and more than one heteroatom. For example, nucleosides comprising morpholino sugar moieties and their use in oligonucleotides have been reported (see, e.g., Braasch et al., Biochemistry, 2002, 41, 4503-4510 and Summerton et al., U.S. Pat. No. 5,698,685; Summerton et al., U.S. Pat. No. 5,166,315; Summerton et al., U.S. Pat. No. 5,185,444; and Summerton et al., U.S. Pat. No. 5,034,506). As used here, the term “morpholino” means a sugar surrogate having the following structure:

In certain embodiments, morpholinos may be modified, for example by adding or altering various substituent groups from the above morpholino structure. Such sugar surrogates are referred to herein as “modified morpholinos.”

In certain embodiments, sugar surrogates comprise acyclic moieties. Examples of nucleosides and oligonucleotides comprising such acyclic sugar surrogates include but are not limited to: peptide nucleic acid (“PNA”), acyclic butyl nucleic acid (see, e.g., Kumar et al., Org. Biomol. Chem., 2013, 11, 5853-5865), and nucleosides and oligonucleotides described in Manoharan et al., WO2011/133876.

Many other bicyclic and tricyclic sugar and sugar surrogate ring systems are known in the art that can be used in modified nucleosides.

2. Certain Modified Nucleobases

In certain embodiments, modified oligonucleotides comprise one or more nucleosides comprising an unmodified nucleobase. In certain embodiments, modified oligonucleotides comprise one or more nucleoside comprising a modified nucleobase. In certain embodiments, modified oligonucleotides comprise one or more nucleoside that does not comprise a nucleobase, referred to as an abasic nucleoside.

In certain embodiments, modified nucleobases are selected from: 5-substituted pyrimidines, 6-azapyrimidines, alkyl or alkynyl substituted pyrimidines, alkyl substituted purines, and N-2, N-6 and 0-6 substituted purines. In certain embodiments, modified nucleobases are selected from: 2-aminopropyladenine, 5-hydroxymethyl cytosine, xanthine, hypoxanthine, 2-aminoadenine, 6-N-methylguanine, 6-N-methyladenine, 2-propyladenine, 2-thiouracil, 2-thiothymine and 2-thiocytosine, 5-propynyl (—C≡C—CH₃) uracil, 5-propynylcytosine, 6-azouracil, 6-azocytosine, 6-azothymine, 5-ribosyluracil (pseudouracil), 4-thiouracil, 8-halo, 8-amino, 8-thiol, 8-thioalkyl, 8-hydroxyl, 8-aza and other 8-substituted purines, 5-halo, particularly 5-bromo, 5-trifluoromethyl, 5-halouracil, and 5-halocytosine, 7-methylguanine, 7-methyladenine, 2-F-adenine, 2-aminoadenine, 7-deazaguanine, 7-deazaadenine, 3-deazaguanine, 3-deazaadenine, 6-N-benzoyladenine, 2-N-isobutyrylguanine, 4-N-benzoylcytosine, 4-N-benzoyluracil, 5-methyl 4-N-benzoylcytosine, 5-methyl 4-N-benzoyluracil, universal bases, hydrophobic bases, promiscuous bases, size-expanded bases, and fluorinated bases. Further modified nucleobases include tricyclic pyrimidines, such as 1,3-diazaphenoxazine-2-one, 1,3-diazaphenothiazine-2-one and 9-(2-aminoethoxy)-1,3-diazaphenoxazine-2-one (G-clamp). Modified nucleobases may also include those in which the purine or pyrimidine base is replaced with other heterocycles, for example 7-deazaadenine, 7-deazaguanosine, 2-aminopyridine and 2-pyridone. Further nucleobases include those disclosed in Merigan et al., U.S. Pat. No. 3,687,808, those disclosed in The Concise Encyclopedia Of Polymer Science And Engineering, Kroschwitz, J. I., Ed., John Wiley & Sons, 1990, 858-859; Englisch et al., Angewandte Chemie, International Edition, 1991, 30, 613; Sanghvi, Y. S., Chapter 15, Antisense Research and Applications, Crooke, S. T. and Lebleu, B., Eds., CRC Press, 1993, 273-288; and those disclosed in Chapters 6 and 15, Antisense Drug Technology, Crooke S. T., Ed., CRC Press, 2008, 163-166 and 442-443.

Publications that teach the preparation of certain of the above noted modified nucleobases as well as other modified nucleobases include without limitation, Manoharan et al., US2003/0158403; Manoharan et al., US2003/0175906; Dinh et al., U.S. Pat. No. 4,845,205; Spielvogel et al., U.S. Pat. No. 5,130,302; Rogers et al., U.S. Pat. No. 5,134,066; Bischofberger et al., U.S. Pat. No. 5,175,273; Urdea et al., U.S. Pat. No. 5,367,066; Benner et al., U.S. Pat. No. 5,432,272; Matteucci et al., U.S. Pat. No. 5,434,257; Gmeiner et al., U.S. Pat. No. 5,457,187; Cook et al., U.S. Pat. No. 5,459,255; Froehler et al., U.S. Pat. No. 5,484,908; Matteucci et al., U.S. Pat. No. 5,502,177; Hawkins et al., U.S. Pat. No. 5,525,711; Haralambidis et al., U.S. Pat. No. 5,552,540; Cook et al., U.S. Pat. No. 5,587,469; Froehler et al., U.S. Pat. No. 5,594,121; Switzer et al., U.S. Pat. No. 5,596,091; Cook et al., U.S. Pat. No. 5,614,617; Froehler et al., U.S. Pat. No. 5,645,985; Cook et al., U.S. Pat. No. 5,681,941; Cook et al., U.S. Pat. No. 5,811,534; Cook et al., U.S. Pat. No. 5,750,692; Cook et al., U.S. Pat. No. 5,948,903; Cook et al., U.S. Pat. No. 5,587,470; Cook et al., U.S. Pat. No. 5,457,191; Matteucci et al., U.S. Pat. No. 5,763,588; Froehler et al., U.S. Pat. No. 5,830,653; Cook et al., U.S. Pat. No. 5,808,027; Cook et al., 6,166,199; and Matteucci et al., U.S. Pat. No. 6,005,096.

3. Certain Modified Internucleoside Linkages

In certain embodiments, nucleosides of modified oligonucleotides may be linked together using any internucleoside linkage. The two main classes of internucleoside linking groups are defined by the presence or absence of a phosphorus atom. Representative phosphorus-containing internucleoside linkages include but are not limited to phosphodiesters, which contain a phosphodiester bond (“P(O₂)═O”) (also referred to as unmodified or naturally occurring linkages), phosphotriesters, methylphosphonates, phosphoramidates, and phosphorothioates (“P(O₂)═S”), and phosphorodithioates (“HS-P═S”). Representative non-phosphorus containing internucleoside linking groups include but are not limited to methylenemethylimino (—CH₂—N(CH₃)—O—CH₂—), thiodiester, thionocarbamate (—O—C(═O)(NH)—S—); siloxane (—O—SiH₂—O—); and N,N′-dimethylhydrazine (—CH₂—N(CH₃)—N(CH₃)—). Modified internucleoside linkages, compared to naturally occurring phosphodiester internucleoside linkages, can be used to alter, typically increase, nuclease resistance of the oligonucleotide. In certain embodiments, internucleoside linkages having a chiral atom can be prepared as a racemic mixture, or as separate enantiomers. Methods of preparation of phosphorous-containing and non-phosphorous-containing internucleoside linkages are well known to those skilled in the art.

Representative internucleoside linkages having a chiral center include but are not limited to alkylphosphonates and phosphorothioates. Modified oligonucleotides comprising internucleoside linkages having a chiral center can be prepared as populations of modified oligonucleotides comprising stereorandom internucleoside linkages, or as populations of modified oligonucleotides comprising phosphorothioate linkages in particular stereochemical configurations. In certain embodiments, populations of modified oligonucleotides comprise phosphorothioate internucleoside linkages wherein all of the phosphorothioate internucleoside linkages are stereorandom. Such modified oligonucleotides can be generated using synthetic methods that result in random selection of the stereochemical configuration of each phosphorothioate linkage. Nonetheless, as is well understood by those of skill in the art, each individual phosphorothioate of each individual oligonucleotide molecule has a defined stereoconfiguration. In certain embodiments, populations of modified oligonucleotides are enriched for modified oligonucleotides comprising one or more particular phosphorothioate internucleoside linkage in a particular, independently selected stereochemical configuration. In certain embodiments, the particular configuration of the particular phosphorothioate linkage is present in at least 65% of the molecules in the population. In certain embodiments, the particular configuration of the particular phosphorothioate linkage is present in at least 70% of the molecules in the population. In certain embodiments, the particular configuration of the particular phosphorothioate linkage is present in at least 80% of the molecules in the population. In certain embodiments, the particular configuration of the particular phosphorothioate linkage is present in at least 90% of the molecules in the population. In certain embodiments, the particular configuration of the particular phosphorothioate linkage is present in at least 99% of the molecules in the population. Such chirally enriched populations of modified oligonucleotides can be generated using synthetic methods known in the art, e.g., methods described in Oka et al., JACS 125, 8307 (2003), Wan et al. Nuc. Acid. Res. 42, 13456 (2014), and WO 2017/015555. In certain embodiments, a population of modified oligonucleotides is enriched for modified oligonucleotides having at least one indicated phosphorothioate in the (Sp) configuration. In certain embodiments, a population of modified oligonucleotides is enriched for modified oligonucleotides having at least one phosphorothioate in the (Rp) configuration. In certain embodiments, modified oligonucleotides comprising (Rp) and/or (Sp) phosphorothioates comprise one or more of the following formulas, respectively, wherein “B” indicates a nucleobase:

Unless otherwise indicated, chiral internucleoside linkages of modified oligonucleotides described herein can be stereorandom or in a particular stereochemical configuration.

Neutral internucleoside linkages include, without limitation, phosphotriesters, methylphosphonates, MMI (3′-CH₂—N(CH₃)—O-5′), amide-3 (3′-CH₂—C(═O)—N(H)-5′), amide-4 (3′-CH₂—N(H)—C(═O)-5′), formacetal (3′-O—CH₂—O-5′), methoxypropyl (MOP), and thioformacetal (3′-S—CH₂—O-5′). Further neutral internucleoside linkages include nonionic linkages comprising siloxane (dialkylsiloxane), carboxylate ester, carboxamide, sulfide, sulfonate ester and amides (See for example: Carbohydrate Modifications in Antisense Research; Y. S. Sanghvi and P. D. Cook, Eds., ACS Symposium Series 580; Chapters 3 and 4, 40-65). Further neutral internucleoside linkages include nonionic linkages comprising mixed N, O, S and CH₂ component parts. In certain embodiments, a neutral internucleoside linkage is any of those described in WO 2021/030778, incorporated by reference herein.

B. Certain Motifs

In certain embodiments, modified oligonucleotides comprise one or more modified nucleosides comprising a modified sugar moiety. In certain embodiments, modified oligonucleotides comprise one or more modified nucleosides comprising a modified nucleobase. In certain embodiments, modified oligonucleotides comprise one or more modified internucleoside linkage. In such embodiments, the modified, unmodified, and differently modified sugar moieties, nucleobases, and/or internucleoside linkages of a modified oligonucleotide define a pattern or motif. In certain embodiments, the patterns of sugar moieties, nucleobases, and internucleoside linkages are each independent of one another. Thus, a modified oligonucleotide may be described by its sugar motif, nucleobase motif and/or internucleoside linkage motif (as used herein, nucleobase motif describes the modifications to the nucleobases independent of the sequence of nucleobases).

1. Certain Sugar Motifs

In certain embodiments, oligonucleotides comprise one or more type of modified sugar and/or unmodified sugar moiety arranged along the oligonucleotide or portion thereof in a defined pattern or sugar motif. In certain instances, such sugar motifs include but are not limited to any of the sugar modifications discussed herein.

In certain embodiments, modified oligonucleotides have a gapmer motif, which is defined by two external regions or “wings” and a central or internal region or “gap.” The three regions of a gapmer motif (the 5′-wing, the gap, and the 3′-wing) form a contiguous sequence of nucleosides wherein at least some of the sugar moieties of the nucleosides of each of the wings differ from at least some of the sugar moieties of the nucleosides of the gap. Specifically, at least the sugar moieties of the nucleosides of each wing that are closest to the gap (the 3′-most nucleoside of the 5′-wing and the 5′-most nucleoside of the 3′-wing) differ from the sugar moiety of the neighboring gap nucleosides, thus defining the boundary between the wings and the gap (i.e., the wing/gap junction). In certain embodiments, the sugar moieties within the gap are the same as one another. In certain embodiments, the gap includes one or more nucleoside having a sugar moiety that differs from the sugar moiety of one or more other nucleosides of the gap. In certain embodiments, the sugar motifs of the two wings are the same as one another (symmetric gapmer). In certain embodiments, the sugar motif of the 5′-wing differs from the sugar motif of the 3′-wing (asymmetric gapmer). In certain embodiments, the wings of a gapmer comprise 1-6 nucleosides. In certain embodiments, each nucleoside of each wing of a gapmer comprises a modified sugar moiety. In certain embodiments, at least one nucleoside of each wing of a gapmer comprises a modified sugar moiety. In certain embodiments, at least two nucleosides of each wing of a gapmer comprises a modified sugar moiety. In certain embodiments, at least three nucleosides of each wing of a gapmer comprises a modified sugar moiety. In certain embodiments, at least four nucleosides of each wing of a gapmer comprises a modified sugar moiety. In certain embodiments, at least five nucleosides of each wing of a gapmer comprises a modified sugar moiety.

In certain embodiments, the gap of a gapmer comprises 7-12 nucleosides. In certain embodiments, each nucleoside of the gap of a gapmer comprises a 2′-deoxyribosyl sugar moiety. In certain embodiments, each nucleoside of the gap of a gapmer comprises a 2′-β-D-deoxyribosyl sugar moiety. In certain embodiments, at least one nucleoside of the gap of a gapmer comprises a modified sugar moiety. In certain embodiments, at least one nucleoside of the gap of a gapmer comprises a 2′-OMe sugar moiety.

In certain embodiments, the gapmer is a deoxy gapmer. In certain embodiments, the nucleosides on the gap side of each wing/gap junction comprise 2′-deoxyribosyl sugar moieties and the nucleosides on the wing sides of each wing/gap junction comprise modified sugar moieties. In certain embodiments, each nucleoside of the gap comprises a 2′-deoxyribosyl sugar moiety. In certain embodiments, each nucleoside of each wing of a gapmer comprises a modified sugar moiety. In certain embodiments, one nucleoside of the gap comprises a modified sugar moiety and each remaining nucleoside of the gap comprises a 2′-deoxyribosyl sugar moiety.

In certain embodiments, modified oligonucleotides comprise or consist of a portion having a fully modified sugar motif. In such embodiments, each nucleoside of the fully modified portion of the modified oligonucleotide comprises a modified sugar moiety. In certain embodiments, each nucleoside of the entire modified oligonucleotide comprises a modified sugar moiety. In certain embodiments, modified oligonucleotides comprise or consist of a portion having a fully modified sugar motif, wherein each nucleoside within the fully modified portion comprises the same modified sugar moiety, referred to herein as a uniformly modified sugar motif. In certain embodiments, a fully modified oligonucleotide is a uniformly modified oligonucleotide. In certain embodiments, each nucleoside of a uniformly modified oligonucleotide comprises the same 2′-modification.

Herein, the lengths (number of nucleosides) of the three regions of a gapmer may be provided using the notation [# of nucleosides in the 5′-wing]-[# of nucleosides in the gap]-[# of nucleosides in the 3′-wing]. Thus, a 5-10-5 gapmer consists of 5 linked nucleosides in each wing and 10 linked nucleosides in the gap. Where such nomenclature is followed by a specific modification, that modification is the modification in each sugar moiety of each wing and the gap nucleosides comprises a 2′-β-D-deoxyribosyl sugar moiety. Thus, a 5-10-5 MOE gapmer consists of 5 linked 2′-MOE nucleosides in the 5′-wing, 10 linked a 2′-β-D-deoxynucleosides in the gap, and 5 linked 2′-MOE nucleosides in the 3′-wing. A 3-10-3 cEt gapmer consists of 3 linked cEt nucleosides in the 5′-wing, 10 linked 2′-β-D-deoxynucleosides in the gap, and 3 linked cEt nucleosides in the 3′-wing. A 5-8-5 gapmer consists of 5 linked nucleosides comprising a modified sugar moiety in the 5′-wing, 8 linked a 2′-β-D-deoxynucleosides in the gap, and 5 linked nucleosides comprising a modified sugar moiety in the 3′-wing. A 5-8-5 or 5-8-4 mixed wing gapmer has at least two different modified sugar moieties in the 5′- and/or the 3′-wing.

In certain embodiments, modified oligonucleotides are 5-10-5 MOE gapmers. In certain embodiments, modified oligonucleotides are 6-10-4 MOE gapmers. In certain embodiments, modified oligonucleotides are 5-8-4 MOE gapmers. In certain embodiments, modified oligonucleotides are X-Y-Z MOE gapmers, wherein X and Z are independently selected from 1, 2, 3, 4, 5, 6, or 7 linked 2′-MOE nucleosides and Y is selected from 7, 8, 9, 10, or 11. linked deoxynucleosides.

In certain embodiments, modified oligonucleotides have a sugar motif selected from the following (5′ to 3′): eeeeeddddddddkkee or eeeeedyddddddkkee, wherein ‘d’ represents a 2′-deoxyribosyl sugar moiety, ‘e’ represents a 2′-MOE sugar moiety, ‘k’ represents a cEt sugar moiety, and ‘y’ represents a 2′-OMe sugar moiety.

2. Certain Nucleobase Motifs

In certain embodiments, oligonucleotides comprise modified and/or unmodified nucleobases arranged along the oligonucleotide or portion thereof in a defined pattern or motif. In certain embodiments, each nucleobase is modified. In certain embodiments, none of the nucleobases are modified. In certain embodiments, each purine or each pyrimidine is modified. In certain embodiments, each adenine is modified. In certain embodiments, each guanine is modified. In certain embodiments, each thymine is modified. In certain embodiments, each uracil is modified. In certain embodiments, each cytosine is modified. In certain embodiments, some or all of the cytosine nucleobases in a modified oligonucleotide are 5-methyl cytosines. In certain embodiments, all of the cytosine nucleobases are 5-methyl cytosines and all of the other nucleobases of the modified oligonucleotide are unmodified nucleobases.

In certain embodiments, modified oligonucleotides comprise a block of modified nucleobases. In certain such embodiments, the block is at the 3′-end of the oligonucleotide. In certain embodiments the block is within 3 nucleosides of the 3′-end of the oligonucleotide. In certain embodiments, the block is at the 5′-end of the oligonucleotide. In certain embodiments the block is within 3 nucleosides of the 5′-end of the oligonucleotide.

In certain embodiments, oligonucleotides having a gapmer motif comprise a nucleoside comprising a modified nucleobase. In certain such embodiments, one nucleoside comprising a modified nucleobase is in the central gap of an oligonucleotide having a gapmer motif. In certain such embodiments, the sugar moiety of said nucleoside is a 2′-deoxyribosyl sugar moiety. In certain embodiments, the modified nucleobase is selected from: a 2-thiopyrimidine and a 5-propynepyrimidine.

3. Certain Internucleoside Linkage Motifs

In certain embodiments, oligonucleotides comprise modified and/or unmodified internucleoside linkages arranged along the oligonucleotide or portion thereof in a defined pattern or motif. In certain embodiments, each internucleoside linking group is a phosphodiester internucleoside linkage (P(O₂)═O). In certain embodiments, each internucleoside linking group of a modified oligonucleotide is a phosphorothioate internucleoside linkage (P(O₂)═S). In certain embodiments, each internucleoside linkage of a modified oligonucleotide is independently selected from a phosphorothioate internucleoside linkage and phosphodiester internucleoside linkage. In certain embodiments, each phosphorothioate internucleoside linkage is independently selected from a stereorandom phosphorothioate, a (Sp) phosphorothioate, and a (Rp) phosphorothioate. In certain embodiments, the sugar motif of a modified oligonucleotide is a gapmer and the internucleoside linkages within the gap are all modified. In certain such embodiments, some or all of the internucleoside linkages in the wings are unmodified phosphodiester internucleoside linkages. In certain embodiments, the terminal internucleoside linkages are modified. In certain embodiments, the sugar motif of a modified oligonucleotide is a gapmer, and the internucleoside linkage motif comprises at least one phosphodiester internucleoside linkage in at least one wing, wherein the at least one phosphodiester linkage is not a terminal internucleoside linkage, and the remaining internucleoside linkages are phosphorothioate internucleoside linkages. In certain such embodiments, all of the phosphorothioate linkages are stereorandom. In certain embodiments, all of the phosphorothioate linkages in the wings are (Sp) phosphorothioates, and the gap comprises at least one Sp, Sp, Rp motif. In certain embodiments, all of the internucleoside linkages are either phosphodiester internucleoside linkages or phosphorothioate internucleoside linkages, and the chiral motif is (5′ to 3′): Sp-o-o-o-Sp-Sp-Sp-Rp-Sp-Sp-Rp-Sp-Sp-Sp-Sp-Sp-Sp-Sp-Sp or Sp-o-o-o-Sp-Sp-Sp-Rp-Sp-Sp-Sp-Sp-Sp-Sp-Sp-Sp-Sp-Sp-Sp, wherein each ‘Sp’ represents a (Sp) phosphorothioate internucleoside linkage, each ‘Rp’ is a Rp internucleoside linkage, and each ‘o’ represents a phosphodiester internucleoside linkage. In certain embodiments, populations of modified oligonucleotides are enriched for modified oligonucleotides comprising such internucleoside linkage motifs.

In certain embodiments, modified oligonucleotides have an internucleoside linkage motif of sooosssssssssssooss, wherein each “s” represents a phosphorothioate internucleoside linkage and each “o” represents a phosphodiester internucleoside linkage. In certain embodiments, modified oligonucleotides have an internucleoside linkage motif of (5′ to 3′): sooooossssssssssoss, wherein each “s” represents a phosphorothioate internucleoside linkage and each “o” represents a phosphodiester internucleoside linkage. In certain embodiments, modified oligonucleotides have an internucleoside linkage motif of (5′ to 3′): sssosssssssssssosss, wherein each “s” represents a phosphorothioate internucleoside linkage and each “o” represents a phosphodiester internucleoside linkage. In certain embodiments, modified oligonucleotides have an internucleoside linkage motif of (5′ to 3′): sssosssssssssoss, wherein each “s” represents a phosphorothioate internucleoside linkage and each “o” represents a phosphodiester internucleoside linkage.

C. Certain Lengths

It is possible to increase or decrease the length of an oligonucleotide without eliminating activity. For example, in Woolf et al. (Proc. Natl. Acad. Sci. USA 89:7305-7309, 1992), a series of oligonucleotides 13-25 nucleobases in length were tested for their ability to induce cleavage of a target nucleic acid in an oocyte injection model. Oligonucleotides 25 nucleobases in length with 8 or 11 mismatch bases near the ends of the oligonucleotides were able to direct specific cleavage of the target nucleic acid, albeit to a lesser extent than the oligonucleotides that contained no mismatches. Similarly, target specific cleavage was achieved using 13 nucleobase oligonucleotides, including those with 1 or 3 mismatches.

In certain embodiments, oligonucleotides (including modified oligonucleotides) can have any of a variety of ranges of lengths. In certain embodiments, oligonucleotides consist of X to Y linked nucleosides, where X represents the fewest number of nucleosides in the range and Y represents the largest number nucleosides in the range. In certain such embodiments, X and Y are each independently selected from 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, and 50; provided that X≤Y. For example, in certain embodiments, oligonucleotides consist of 12 to 13, 12 to 14, 12 to 15, 12 to 16, 12 to 17, 12 to 18, 12 to 19, 12 to 20, 12 to 21, 12 to 22, 12 to 23, 12 to 24, 12 to 25, 12 to 26, 12 to 27, 12 to 28, 12 to 29, 12 to 30, 13 to 14, 13 to 15, 13 to 16, 13 to 17, 13 to 18, 13 to 19, 13 to 20, 13 to 21, 13 to 22, 13 to 23, 13 to 24, 13 to 25, 13 to 26, 13 to 27, 13 to 28, 13 to 29, 13 to 30, 14 to 15, 14 to 16, 14 to 17, 14 to 18, 14 to 19, 14 to 20, 14 to 21, 14 to 22, 14 to 23, 14 to 24, 14 to 25, 14 to 26, 14 to 27, 14 to 28, 14 to 29, 14 to 30, 15 to 16, 15 to 17, 15 to 18, 15 to 19, 15 to 20, 15 to 21, 15 to 22, 15 to 23, 15 to 24, 15 to 25, 15 to 26, 15 to 27, 15 to 28, 15 to 29, 15 to 30, 16 to 17, 16 to 18, 16 to 19, 16 to 20, 16 to 21, 16 to 22, 16 to 23, 16 to 24, 16 to 25, 16 to 26, 16 to 27, 16 to 28, 16 to 29, 16 to 30, 17 to 18, 17 to 19, 17 to 20, 17 to 21, 17 to 22, 17 to 23, 17 to 24, 17 to 25, 17 to 26, 17 to 27, 17 to 28, 17 to 29, 17 to 30, 18 to 19, 18 to 20, 18 to 21, 18 to 22, 18 to 23, 18 to 24, 18 to 25, 18 to 26, 18 to 27, 18 to 28, 18 to 29, 18 to 30, 19 to 20, 19 to 21, 19 to 22, 19 to 23, 19 to 24, 19 to 25, 19 to 26, 19 to 29, 19 to 28, 19 to 29, 19 to 30, 20 to 21, 20 to 22, 20 to 23, 20 to 24, 20 to 25, 20 to 26, 20 to 27, 20 to 28, 20 to 29, 20 to 30, 21 to 22, 21 to 23, 21 to 24, 21 to 25, 21 to 26, 21 to 27, 21 to 28, 21 to 29, 21 to 30, 22 to 23, 22 to 24, 22 to 25, 22 to 26, 22 to 27, 22 to 28, 22 to 29, 22 to 30, 23 to 24, 23 to 25, 23 to 26, 23 to 27, 23 to 28, 23 to 29, 23 to 30, 24 to 25, 24 to 26, 24 to 27, 24 to 28, 24 to 29, 24 to 30, 25 to 26, 25 to 27, 25 to 28, 25 to 29, 25 to 30, 26 to 27, 26 to 28, 26 to 29, 26 to 30, 27 to 28, 27 to 29, 27 to 30, 28 to 29, 28 to 30, or 29 to 30 linked nucleosides.

D. Certain Modified Oligonucleotides

In certain embodiments, the above modifications (sugar, nucleobase, internucleoside linkage) are incorporated into a modified oligonucleotide. In certain embodiments, modified oligonucleotides are characterized by their modification motifs and overall lengths. In certain embodiments, such parameters are each independent of one another. Thus, unless otherwise indicated, each internucleoside linkage of an oligonucleotide having a gapmer sugar motif may be modified or unmodified and may or may not follow the gapmer modification pattern of the sugar modifications. For example, the internucleoside linkages within the wing regions of a sugar gapmer may be the same or different from one another and may be the same or different from the internucleoside linkages of the gap region of the sugar motif. Likewise, such sugar gapmer oligonucleotides may comprise one or more modified nucleobase independent of the gapmer pattern of the sugar modifications. Unless otherwise indicated, all modifications are independent of nucleobase sequence.

E. Certain Populations of Modified Oligonucleotides

Populations of modified oligonucleotides in which all of the modified oligonucleotides of the population have the same molecular formula can be stereorandom populations or chirally enriched populations. All of the chiral centers of all of the modified oligonucleotides are stereorandom in a stereorandom population. In a chirally enriched population, at least one particular chiral center is not stereorandom in the modified oligonucleotides of the population. In certain embodiments, the modified oligonucleotides of a chirally enriched population are enriched for β-D ribosyl sugar moieties, and all of the phosphorothioate internucleoside linkages are stereorandom. In certain embodiments, the modified oligonucleotides of a chirally enriched population are enriched for both β-D ribosyl sugar moieties and at least one, particular phosphorothioate internucleoside linkage in a particular stereochemical configuration.

F. Nucleobase Sequence

In certain embodiments, oligonucleotides (unmodified or modified oligonucleotides) are further described by their nucleobase sequence. In certain embodiments oligonucleotides have a nucleobase sequence that is complementary to a second oligonucleotide or an identified reference nucleic acid, such as a target nucleic acid. In certain such embodiments, a portion of an oligonucleotide has a nucleobase sequence that is complementary to a second oligonucleotide or an identified reference nucleic acid, such as a target nucleic acid. In certain embodiments, the nucleobase sequence of a portion or entire length of an oligonucleotide is at least 50%, at least 60%, at least 70%, at least 80%, at least 85%, at least 90%, at least 95%, or 100% complementary to the second oligonucleotide or nucleic acid, such as a target nucleic acid.

II. Certain Oligomeric Compounds

In certain embodiments, provided herein are oligomeric compounds, which consist of an oligonucleotide (modified or unmodified) and optionally one or more conjugate groups and/or terminal groups. Conjugate groups consist of one or more conjugate moiety and a conjugate linker which links the conjugate moiety to the oligonucleotide. Conjugate groups may be attached to either or both ends of an oligonucleotide and/or at any internal position. In certain embodiments, conjugate groups are attached to the 2′-position of a nucleoside of a modified oligonucleotide. In certain embodiments, conjugate groups that are attached to either or both ends of an oligonucleotide are terminal groups. In certain such embodiments, conjugate groups or terminal groups are attached at the 3′ and/or 5′-end of oligonucleotides. In certain such embodiments, conjugate groups (or terminal groups) are attached at the 3′-end of oligonucleotides. In certain embodiments, conjugate groups are attached near the 3′-end of oligonucleotides. In certain embodiments, conjugate groups (or terminal groups) are attached at the 5′-end of oligonucleotides. In certain embodiments, conjugate groups are attached near the 5′-end of oligonucleotides.

Examples of terminal groups include but are not limited to conjugate groups, capping groups, phosphate moieties, protecting groups, modified or unmodified nucleosides, and two or more nucleosides that are independently modified or unmodified.

A. Certain Conjugate Groups

In certain embodiments, oligonucleotides are covalently attached to one or more conjugate groups. In certain embodiments, conjugate groups modify one or more properties of the attached oligonucleotide, including but not limited to pharmacodynamics, pharmacokinetics, stability, binding, absorption, tissue distribution, cellular distribution, cellular uptake, charge and clearance. In certain embodiments, conjugate groups impart a new property on the attached oligonucleotide, e.g., fluorophores or reporter groups that enable detection of the oligonucleotide. Certain conjugate groups and conjugate moieties have been described previously, for example: cholesterol moiety (Letsinger et al., Proc. Natl. Acad. Sci. USA, 1989, 86, 6553-6556), cholic acid (Manoharan et al., Bioorg. Med. Chem. Lett., 1994, 4, 1053-1060), a thioether, e.g., hexyl-S-tritylthiol (Manoharan et al., Ann. N.Y. Acad. Sci., 1992, 660, 306-309; Manoharan et al., Bioorg. Med. Chem. Lett., 1993, 3, 2765-2770), a thiocholesterol (Oberhauser et al., Nucl. Acids Res., 1992, 20, 533-538), an aliphatic chain, e.g., do-decan-diol or undecyl residues (Saison-Behmoaras et al., EMBO J., 1991, 10, 1111-1118; Kabanov et al., FEBS Lett., 1990, 259, 327-330; Svinarchuk et al., Biochimie, 1993, 75, 49-54), a phospholipid, e.g., di-hexadecyl-rac-glycerol or triethyl-ammonium 1,2-di-O-hexadecyl-rac-glycero-3-H-phosphonate (Manoharan et al., Tetrahedron Lett., 1995, 36, 3651-3654; Shea et al., Nucl. Acids Res., 1990, 18, 3777-3783), a polyamine or a polyethylene glycol chain (Manoharan et al., Nucleosides & Nucleotides, 1995, 14, 969-973), or adamantane acetic acid a palmityl moiety (Mishra et al., Biochim. Biophys. Acta, 1995, 1264, 229-237), an octadecylamine or hexylamino-carbonyl-oxycholesterol moiety (Crooke et al., J. Pharmacol. Exp. Ther., 1996, 277, 923-937), a tocopherol group (Nishina et al., Molecular Therapy Nucleic Acids, 2015, 4, e220; and Nishina et al., Molecular Therapy, 2008, 16, 734-740), or a GalNAc cluster (e.g., WO2014/179620).

1. Conjugate Moieties

Conjugate moieties include, without limitation, intercalators, reporter molecules, polyamines, polyamides, peptides, carbohydrates, vitamin moieties, polyethylene glycols, thioethers, polyethers, cholesterols, thiocholesterols, cholic acid moieties, folate, lipids, lipophilic groups, phospholipids, biotin, phenazine, phenanthridine, anthraquinone, adamantane, acridine, fluoresceins, rhodamines, coumarins, fluorophores, and dyes.

In certain embodiments, a conjugate moiety comprises an active drug substance, for example, aspirin, warfarin, phenylbutazone, ibuprofen, suprofen, fen-bufen, ketoprofen, (S)-(+)-pranoprofen, carprofen, dansylsarcosine, 2,3,5-triiodobenzoic acid, fingolimod, flufenamic acid, folinic acid, a benzothiadiazide, chlorothiazide, a diazepine, indo-methicin, a barbiturate, a cephalosporin, a sulfa drug, an antidiabetic, an antibacterial or an antibiotic.

2. Conjugate Linkers

Conjugate moieties are attached to oligonucleotides through conjugate linkers. In certain oligomeric compounds, the conjugate linker is a single chemical bond (i.e., the conjugate moiety is attached directly to an oligonucleotide through a single bond). In certain embodiments, the conjugate linker comprises a chain structure, such as a hydrocarbyl chain, or an oligomer of repeating units such as ethylene glycol, nucleosides, or amino acid units.

In certain embodiments, a conjugate linker comprises one or more groups selected from alkyl, amino, oxo, amide, disulfide, polyethylene glycol, ether, thioether, and hydroxylamino. In certain such embodiments, the conjugate linker comprises groups selected from alkyl, amino, oxo, amide and ether groups. In certain embodiments, the conjugate linker comprises groups selected from alkyl and amide groups. In certain embodiments, the conjugate linker comprises groups selected from alkyl and ether groups. In certain embodiments, the conjugate linker comprises at least one phosphorus moiety. In certain embodiments, the conjugate linker comprises at least one phosphate group. In certain embodiments, the conjugate linker includes at least one neutral linking group.

In certain embodiments, conjugate linkers, including the conjugate linkers described above, are bifunctional linking moieties, e.g., those known in the art to be useful for attaching conjugate groups to parent compounds, such as the oligonucleotides provided herein. In general, a bifunctional linking moiety comprises at least two functional groups. One of the functional groups is selected to bind to a particular site on a parent compound and the other is selected to bind to a conjugate group. Examples of functional groups used in a bifunctional linking moiety include but are not limited to electrophiles for reacting with nucleophilic groups and nucleophiles for reacting with electrophilic groups. In certain embodiments, bifunctional linking moieties comprise one or more groups selected from amino, hydroxyl, carboxylic acid, thiol, alkyl, alkenyl, and alkynyl.

Examples of conjugate linkers include but are not limited to pyrrolidine, 8-amino-3,6-dioxaoctanoic acid (ADO), succinimidyl 4-(N-maleimidomethyl) cyclohexane-1-carboxylate (SMCC) and 6-aminohexanoic acid (AHEX or AHA). Other conjugate linkers include but are not limited to substituted or unsubstituted C₁-C₁₀ alkyl, substituted or unsubstituted C₂-C₁₀ alkenyl or substituted or unsubstituted C₂-C₁₀ alkynyl, wherein a nonlimiting list of preferred substituent groups includes hydroxyl, amino, alkoxy, carboxy, benzyl, phenyl, nitro, thiol, thioalkoxy, halogen, alkyl, aryl, alkenyl and alkynyl.

In certain embodiments, conjugate linkers comprise 1-10 linker-nucleosides. In certain embodiments, conjugate linkers comprise 2-5 linker-nucleosides. In certain embodiments, conjugate linkers comprise exactly 3 linker-nucleosides. In certain embodiments, conjugate linkers comprise the TCA motif. In certain embodiments, such linker-nucleosides are modified nucleosides. In certain embodiments such linker-nucleosides comprise a modified sugar moiety. In certain embodiments, linker-nucleosides are unmodified. In certain embodiments, linker-nucleosides comprise an optionally protected heterocyclic base selected from a purine, substituted purine, pyrimidine or substituted pyrimidine. In certain embodiments, a cleavable moiety is a nucleoside selected from uracil, thymine, cytosine, 4-N-benzoylcytosine, 5-methyl cytosine, 4-N-benzoyl-5-methyl cytosine, adenine, 6-N-benzoyladenine, guanine and 2-N-isobutyrylguanine. It is typically desirable for linker-nucleosides to be cleaved from the oligomeric compound after it reaches a target tissue. Accordingly, linker-nucleosides are typically linked to one another and to the remainder of the oligomeric compound through cleavable bonds. In certain embodiments, such cleavable bonds are phosphodiester bonds.

Herein, linker-nucleosides are not considered to be part of the oligonucleotide. Accordingly, in embodiments in which an oligomeric compound comprises an oligonucleotide consisting of a specified number or range of linked nucleosides and/or a specified percent complementarity to a reference nucleic acid and the oligomeric compound also comprises a conjugate group comprising a conjugate linker comprising linker-nucleosides, those linker-nucleosides are not counted toward the length of the oligonucleotide and are not used in determining the percent complementarity of the oligonucleotide for the reference nucleic acid. For example, an oligomeric compound may comprise (1) a modified oligonucleotide consisting of 8-30 nucleosides and (2) a conjugate group comprising 1-10 linker-nucleosides that are contiguous with the nucleosides of the modified oligonucleotide. The total number of contiguous linked nucleosides in such an oligomeric compound is more than 30. Alternatively, an oligomeric compound may comprise a modified oligonucleotide consisting of 8-30 nucleosides and no conjugate group. The total number of contiguous linked nucleosides in such an oligomeric compound is no more than 30. Unless otherwise indicated conjugate linkers comprise no more than 10 linker-nucleosides. In certain embodiments, conjugate linkers comprise no more than 5 linker-nucleosides. In certain embodiments, conjugate linkers comprise no more than 3 linker-nucleosides. In certain embodiments, conjugate linkers comprise no more than 2 linker-nucleosides. In certain embodiments, conjugate linkers comprise no more than 1 linker-nucleoside.

In certain embodiments, it is desirable for a conjugate group to be cleaved from the oligonucleotide. For example, in certain circumstances oligomeric compounds comprising a particular conjugate moiety are better taken up by a particular cell type, but once the oligomeric compound has been taken up, it is desirable that the conjugate group be cleaved to release the unconjugated or parent oligonucleotide. Thus, certain conjugate linkers may comprise one or more cleavable moieties. In certain embodiments, a cleavable moiety is a cleavable bond. In certain embodiments, a cleavable moiety is a group of atoms comprising at least one cleavable bond. In certain embodiments, a cleavable moiety comprises a group of atoms having one, two, three, four, or more than four cleavable bonds. In certain embodiments, a cleavable moiety is selectively cleaved inside a cell or subcellular compartment, such as a lysosome. In certain embodiments, a cleavable moiety is selectively cleaved by endogenous enzymes, such as nucleases.

In certain embodiments, a cleavable bond is selected from among: an amide, an ester, an ether, one or both esters of a phosphodiester, a phosphate ester, a carbamate, or a disulfide. In certain embodiments, a cleavable bond is one or both of the esters of a phosphodiester. In certain embodiments, a cleavable moiety comprises a phosphate or phosphodiester. In certain embodiments, the cleavable moiety is a phosphate or phosphodiester linkage between an oligonucleotide and a conjugate moiety or conjugate group.

In certain embodiments, a cleavable moiety comprises or consists of one or more linker-nucleosides. In certain such embodiments, the one or more linker-nucleosides are linked to one another and/or to the remainder of the oligomeric compound through cleavable bonds. In certain embodiments, such cleavable bonds are unmodified phosphodiester bonds. In certain embodiments, a cleavable moiety is 2′-deoxynucleoside that is attached to either the 3′ or 5′-terminal nucleoside of an oligonucleotide by a phosphodiester internucleoside linkage and covalently attached to the remainder of the conjugate linker or conjugate moiety by a phosphate or phosphorothioate linkage. In certain such embodiments, the cleavable moiety is 2′-deoxyadenosine.

3. Cell-Targeting Moieties

In certain embodiments, a conjugate group comprises a cell-targeting moiety. In certain embodiments, a conjugate group has the general formula:

wherein n is from 1 to about 3, m is 0 when n is 1, m is 1 when n is 2 or greater, j is 1 or 0, and k is 1 or 0.

In certain embodiments, n is 1, j is 1 and k is 0. In certain embodiments, n is 1, j is 0 and k is 1. In certain embodiments, n is 1, j is 1 and k is 1. In certain embodiments, n is 2, j is 1 and k is 0. In certain embodiments, n is 2, j is 0 and k is 1. In certain embodiments, n is 2, j is 1 and k is 1. In certain embodiments, n is 3, j is 1 and k is 0. In certain embodiments, n is 3, j is 0 and k is 1. In certain embodiments, n is 3, j is 1 and k is 1.

In certain embodiments, conjugate groups comprise cell-targeting moieties that have at least one tethered ligand. In certain embodiments, cell-targeting moieties comprise two tethered ligands covalently attached to a branching group. In certain embodiments, cell-targeting moieties comprise three tethered ligands covalently attached to a branching group.

B. Certain Terminal Groups

In certain embodiments, oligomeric compounds comprise one or more terminal groups. In certain such embodiments, oligomeric compounds comprise a stabilized 5′-phosphate. Stabilized 5′-phosphates include, but are not limited to 5′-phosphonates, including, but not limited to 5′-vinylphosphonates. In certain embodiments, terminal groups comprise one or more abasic nucleosides and/or inverted nucleosides. In certain embodiments, terminal groups comprise one or more 2′-linked nucleosides. In certain such embodiments, the 2′-linked nucleoside is an abasic nucleoside.

III. Oligomeric Duplexes

In certain embodiments, oligomeric compounds described herein comprise an oligonucleotide, having a nucleobase sequence complementary to that of a target nucleic acid. In certain embodiments, an oligomeric compound is paired with a second oligomeric compound to form an oligomeric duplex. Such oligomeric duplexes comprise a first oligomeric compound having a portion complementary to a target nucleic acid and a second oligomeric compound having a portion complementary to the first oligomeric compound. In certain embodiments, the first oligomeric compound of an oligomeric duplex comprises or consists of (1) a modified or unmodified oligonucleotide and optionally a conjugate group and (2) a second modified or unmodified oligonucleotide and optionally a conjugate group. Either or both oligomeric compounds of an oligomeric duplex may comprise a conjugate group. The oligonucleotides of each oligomeric compound of an oligomeric duplex may include non-complementary overhanging nucleosides.

IV. Antisense Activity

In certain embodiments, oligomeric compounds and oligomeric duplexes are capable of hybridizing to a target nucleic acid, resulting in at least one antisense activity; such oligomeric compounds and oligomeric duplexes are antisense compounds. In certain embodiments, antisense compounds have antisense activity when they reduce the amount or activity of a target nucleic acid by 25% or more in the standard cell assay. In certain embodiments, antisense compounds selectively affect one or more target nucleic acid. Such antisense compounds comprise a nucleobase sequence that hybridizes to one or more target nucleic acid, resulting in one or more desired antisense activity and does not hybridize to one or more non-target nucleic acid or does not hybridize to one or more non-target nucleic acid in such a way that results in significant undesired antisense activity.

In certain antisense activities, hybridization of an antisense compound to a target nucleic acid results in recruitment of a protein that cleaves the target nucleic acid. For example, certain antisense compounds result in RNase H mediated cleavage of the target nucleic acid. RNase H is a cellular endonuclease that cleaves the RNA strand of an RNA:DNA duplex. The DNA in such an RNA:DNA duplex need not be unmodified DNA. In certain embodiments, described herein are antisense compounds that are sufficiently “DNA-like” to elicit RNase H activity. In certain embodiments, one or more non-DNA-like nucleoside in the gap of a gapmer is tolerated.

In certain antisense activities, an antisense compound or a portion of an antisense compound is loaded into an RNA-induced silencing complex (RISC), ultimately resulting in cleavage of the target nucleic acid. For example, certain antisense compounds result in cleavage of the target nucleic acid by Argonaute. Antisense compounds that are loaded into RISC are RNAi compounds. RNAi compounds may be double-stranded (siRNA) or single-stranded (ssRNA).

In certain embodiments, hybridization of an antisense compound to a target nucleic acid does not result in recruitment of a protein that cleaves that target nucleic acid. In certain embodiments, hybridization of the antisense compound to the target nucleic acid results in alteration of splicing of the target nucleic acid. In certain embodiments, hybridization of an antisense compound to a target nucleic acid results in inhibition of a binding interaction between the target nucleic acid and a protein or other nucleic acid. In certain embodiments, hybridization of an antisense compound to a target nucleic acid results in alteration of translation of the target nucleic acid.

Antisense activities may be observed directly or indirectly. In certain embodiments, observation or detection of an antisense activity involves observation or detection of a change in an amount of a target nucleic acid or protein encoded by such target nucleic acid, a change in the ratio of splice variants of a nucleic acid or protein and/or a phenotypic change in a cell or subject.

V. Certain Target Nucleic Acids

In certain embodiments, oligomeric compounds comprise or consist of an oligonucleotide comprising a portion that is complementary to a target nucleic acid. In certain embodiments, the target nucleic acid is an endogenous RNA molecule. In certain embodiments, the target nucleic acid encodes a protein. In certain such embodiments, the target nucleic acid is selected from: a mature mRNA and a pre-mRNA, including intronic, exonic and untranslated regions. In certain embodiments, the target nucleic acid is a mature mRNA. In certain embodiments, the target nucleic acid is a pre-mRNA. In certain such embodiments, the target region is entirely within an intron. In certain embodiments, the target region spans an intron/exon junction. In certain embodiments, the target region is at least 50% within an intron.

A. Complementarity/Mismatches to the Target Nucleic Acid

It is possible to introduce mismatch bases without eliminating activity. For example, Gautschi et al (J. Natl. Cancer Inst. 93:463-471, March 2001) demonstrated the ability of an oligonucleotide having 100% complementarity to the bcl-2 mRNA and having 3 mismatches to the bcl-xL mRNA to reduce the expression of both bcl-2 and bcl-xL in vitro and in vivo. Furthermore, this oligonucleotide demonstrated potent anti-tumor activity in vivo. Maher and Dolnick (Nuc. Acid. Res. 16:3341-3358, 1988) tested a series of tandem 14 nucleobase oligonucleotides, and 28 and 42 nucleobase oligonucleotides comprised of the sequence of two or three of the tandem oligonucleotides, respectively, for their ability to arrest translation of human DHFR in a rabbit reticulocyte assay. Each of the three 14 nucleobase oligonucleotides alone was able to inhibit translation, albeit at a more modest level than the 28 or 42 nucleobase oligonucleotides.

In certain embodiments, oligonucleotides are complementary to the target nucleic acid over the entire length of the oligonucleotide. In certain embodiments, oligonucleotides are 99%, 95%, 90%, 85%, or 80% complementary to the target nucleic acid. In certain embodiments, oligonucleotides are at least 80% complementary to the target nucleic acid over the entire length of the oligonucleotide and comprise a portion that is 100% or fully complementary to a target nucleic acid. In certain embodiments, the portion of full complementarity is 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, or 24 nucleobases in length.

In certain embodiments, oligonucleotides comprise one or more mismatched nucleobases relative to the target nucleic acid. In certain embodiments, antisense activity against the target is reduced by such mismatch, but activity against a non-target is reduced by a greater amount. Thus, in certain embodiments selectivity of the oligonucleotide is improved. In certain embodiments, the mismatch is specifically positioned within an oligonucleotide having a gapmer motif. In certain embodiments, the mismatch is at position 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11 from the 5′-end of the gap region. In certain embodiments, the mismatch is at position 1, 2, 3, 4, 5, or 6 from the 5′-end of the 5′ wing region or the 3′ wing region.

B. ATXN1

In certain embodiments, oligomeric compounds comprise or consist of an oligonucleotide that is complementary to a target nucleic acid, wherein the target nucleic acid is an ATXN1 nucleic acid. In certain embodiments, ATXN1 nucleic acid has the sequence set forth in SEQ ID NO: 1 (GENBANK Accession No. NM_000332.3), SEQ ID NO: 2 (the complement of GENBANK Accession No. NC_000006.12 truncated from nucleotides 16296001 to 16764000), SEQ ID NO: 3 (GENBANK Accession No. NM_001128164.1), SEQ ID NO: 4 (GENBANK Accession No. BC011026.1), SEQ ID NO: 5 (GENBANK Accession No. BC029401.1), or SEQ ID NO: 6 (GENBANK Accession No. BC047894.1).

In certain embodiments, contacting a cell with an oligomeric compound complementary to any of SEQ ID NO: 1-6 reduces the amount of ATXN1 RNA in a cell. In certain embodiments, contacting a cell with an oligomeric compound complementary to any of SEQ ID NO: 1-6 reduces the amount of ATXN1 in a cell. In certain embodiments, the cell is in vitro. In certain embodiments, the cell is in a subject. In certain embodiments, the oligomeric compound consists of a modified oligonucleotide. In certain embodiments, contacting a cell in a subject with an oligomeric compound complementary to any of SEQ ID NO: 1-6 ameliorates one or more symptom or hallmark of a neurodegenerative disease. In certain embodiments, the neurodegenerative disease is SCA1. In certain embodiments, the symptom or hallmark is selected from gait and limb ataxia, cognitive impairments, difficulty with speaking and swallowing, atrophy of the cerebellum and brainstem in magnetic resonance imaging (MRI), neurochemical abnormalities in the cerebellum and brainstem detected via magnetic resonance spectroscopy (MRS), and death within 10-15 years of symptom onset.

In certain embodiments, an oligomeric compound complementary to any of SEQ ID NO: 1-6 is capable of reducing the detectable amount of ATXN1 RNA in vitro by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90% when administered according to the standard cell assay. In certain embodiments, an oligomeric compound complementary to SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, or SEQ ID NO: 6 is capable of decreasing the amount of ATXN1 in vitro by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90% when administered according to the standard cell assay. In certain embodiments, an oligomeric compound complementary to SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, or SEQ ID NO: 6 is capable of reducing the detectable amount of ATXN1 RNA in the CSF of a subject by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90%. In certain embodiments, an oligomeric compound complementary to SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, or SEQ ID NO: 6 is capable of decreasing the detectable amount of ATXN1 in the CSF of a subject by at least 10%, at least 20%, at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, or at least 90%.

C. Certain Target Nucleic Acids in Certain Tissues

In certain embodiments, oligomeric compounds comprise or consist of an oligonucleotide comprising a portion that is complementary to a target nucleic acid, wherein the target nucleic acid is expressed in a pharmacologically relevant tissue. In certain embodiments, the pharmacologically relevant tissues are the cells and tissues that comprise the central nervous system. Such tissues include the cortex, cerebellum, and brainstem.

VI. Certain Pharmaceutical Compositions

In certain embodiments, described herein are pharmaceutical compositions comprising one or more oligomeric compounds. In certain embodiments, the one or more oligomeric compounds each consists of a modified oligonucleotide. In certain embodiments, the pharmaceutical composition comprises a pharmaceutically acceptable diluent or carrier. In certain embodiments, a pharmaceutical composition comprises or consists of a sterile saline solution and one or more oligomeric compound. In certain embodiments, the sterile saline is pharmaceutical grade saline. In certain embodiments, a pharmaceutical composition comprises or consists of one or more oligomeric compound and sterile water. In certain embodiments, the sterile water is pharmaceutical grade water. In certain embodiments, a pharmaceutical composition comprises or consists of one or more oligomeric compound and phosphate-buffered saline (PBS). In certain embodiments, the sterile PBS is pharmaceutical grade PBS. In certain embodiments, a pharmaceutical composition comprises or consists of one or more oligomeric compound and artificial cerebrospinal fluid. In certain embodiments, the artificial cerebrospinal fluid is pharmaceutical grade.

In certain embodiments, a pharmaceutical composition comprises a modified oligonucleotide and artificial cerebrospinal fluid. In certain embodiments, a pharmaceutical composition consists of a modified oligonucleotide and artificial cerebrospinal fluid. In certain embodiments, a pharmaceutical composition consists essentially of a modified oligonucleotide and artificial cerebrospinal fluid. In certain embodiments, the artificial cerebrospinal fluid is pharmaceutical grade.

In certain embodiments, pharmaceutical compositions comprise one or more oligomeric compound and one or more excipients. In certain embodiments, excipients are selected from water, salt solutions, alcohol, polyethylene glycols, gelatin, lactose, amylase, magnesium stearate, talc, silicic acid, viscous paraffin, hydroxymethylcellulose and polyvinylpyrrolidone.

In certain embodiments, oligomeric compounds may be admixed with pharmaceutically acceptable active and/or inert substances for the preparation of pharmaceutical compositions or formulations. Compositions and methods for the formulation of pharmaceutical compositions depend on a number of criteria, including, but not limited to, route of administration, extent of disease, or dose to be administered.

In certain embodiments, pharmaceutical compositions comprising an oligomeric compound encompass any pharmaceutically acceptable salts of the oligomeric compound, esters of the oligomeric compound, or salts of such esters. In certain embodiments, pharmaceutical compositions comprising oligomeric compounds comprising one or more oligonucleotide, upon administration to a subject, including a human, are capable of providing (directly or indirectly) the biologically active metabolite or residue thereof. Accordingly, for example, the disclosure is also drawn to pharmaceutically acceptable salts of oligomeric compounds, prodrugs, pharmaceutically acceptable salts of such prodrugs, and other bioequivalents. Suitable pharmaceutically acceptable salts include, but are not limited to, sodium and potassium salts. In certain embodiments, prodrugs comprise one or more conjugate group attached to an oligonucleotide, wherein the conjugate group is cleaved by endogenous nucleases within the body.

Lipid moieties have been used in nucleic acid therapies in a variety of methods. In certain such methods, the nucleic acid, such as an oligomeric compound, is introduced into preformed liposomes or lipoplexes made of mixtures of cationic lipids and neutral lipids. In certain methods, DNA complexes with mono- or poly-cationic lipids are formed without the presence of a neutral lipid. In certain embodiments, a lipid moiety is selected to increase distribution of a pharmaceutical agent to a particular cell or tissue. In certain embodiments, a lipid moiety is selected to increase distribution of a pharmaceutical agent to fat tissue. In certain embodiments, a lipid moiety is selected to increase distribution of a pharmaceutical agent to muscle tissue.

In certain embodiments, pharmaceutical compositions comprise a delivery system. Examples of delivery systems include, but are not limited to, liposomes and emulsions. Certain delivery systems are useful for preparing certain pharmaceutical compositions including those comprising hydrophobic compounds. In certain embodiments, certain organic solvents such as dimethylsulfoxide are used.

In certain embodiments, pharmaceutical compositions comprise one or more tissue-specific delivery molecules designed to deliver the one or more pharmaceutical agents comprising an oligomeric compound provided herein to specific tissues or cell types. For example, in certain embodiments, pharmaceutical compositions include liposomes coated with a tissue-specific antibody.

In certain embodiments, pharmaceutical compositions comprise a co-solvent system. Certain of such co-solvent systems comprise, for example, benzyl alcohol, a nonpolar surfactant, a water-miscible organic polymer, and an aqueous phase. In certain embodiments, such co-solvent systems are used for hydrophobic compounds. A non-limiting example of such a co-solvent system is the VPD co-solvent system, which is a solution of absolute ethanol comprising 3% w/v benzyl alcohol, 8% w/v of the nonpolar surfactant Polysorbate 80™ and 65% w/v polyethylene glycol 300. The proportions of such co-solvent systems may be varied considerably without significantly altering their solubility and toxicity characteristics. Furthermore, the identity of co-solvent components may be varied: for example, other surfactants may be used instead of Polysorbate 80™; the fraction size of polyethylene glycol may be varied; other biocompatible polymers may replace polyethylene glycol, e.g., polyvinyl pyrrolidone; and other sugars or polysaccharides may substitute for dextrose.

In certain embodiments, pharmaceutical compositions are prepared for oral administration. In certain embodiments, pharmaceutical compositions are prepared for buccal administration. In certain embodiments, a pharmaceutical composition is prepared for administration by injection (e.g., intravenous, subcutaneous, intramuscular, intrathecal (IT), intracerebroventricular (ICV), etc.). In certain of such embodiments, a pharmaceutical composition comprises a carrier and is formulated in aqueous solution, such as water or physiologically compatible buffers such as Hanks's solution, Ringer's solution, or physiological saline buffer. In certain embodiments, other ingredients are included (e.g., ingredients that aid in solubility or serve as preservatives). In certain embodiments, injectable suspensions are prepared using appropriate liquid carriers, suspending agents and the like. Certain pharmaceutical compositions for injection are presented in unit dosage form, e.g., in ampoules or in multi-dose containers. Certain pharmaceutical compositions for injection are suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulatory agents such as suspending, stabilizing and/or dispersing agents. Certain solvents suitable for use in pharmaceutical compositions for injection include, but are not limited to, lipophilic solvents and fatty oils, such as sesame oil, synthetic fatty acid esters, such as ethyl oleate or triglycerides, and liposomes.

VII. Certain Compositions

1. Compound No. 994509

In certain embodiments, Compound No. 994509 is characterized as a 5-10-5 MOE gapmer having a sequence of (from 5′ to 3′) GCACGGTATTAGTGTCTTCA (SEQ ID NO: 126), wherein each of nucleosides 1-5 and 16-20 (from 5′ to 3′) are 2′-MOE nucleosides and each of nucleosides 6-15 are 2′-β-D-deoxynucleosides, wherein the internucleoside linkages between nucleosides 2 to 3, 3 to 4, 4 to 5, 16 to 17, and 17 to 18 are phosphodiester internucleoside linkages and the internucleoside linkages between nucleosides 1 to 2, 5 to 6, 6 to 7, 7 to 8, 8 to 9, 9 to 10, 10 to 11, 11 to 12, 12 to 13, 13 to 14, 14 to 15, 15 to 16, 18 to 19, and 19 to 20 are phosphorothioate internucleoside linkages, and wherein each cytosine is a 5-methyl cytosine.

In certain embodiments, Compound No. 994509 is represented by the following chemical notation (5′ to 3′): Ges ^(m)Ceo Aeo ^(m)Ceo Ges Gds Tds Ads Tds Tds Ads Gds Tds Gds Tds ^(m)Ceo Teo Tes ^(m)Ces Ae (SEQ ID NO: 126), wherein,

A=an adenine nucleobase,

^(m)C=a 5-methyl cytosine nucleobase,

G=a guanine nucleobase,

T=a thymine nucleobase,

e=a 2′-MOE sugar moiety,

d=a 2′-β-D deoxyribosyl sugar moiety,

s=a phosphorothioate internucleoside linkage, and

o=a phosphodiester internucleoside linkage.

In certain embodiments, Compound No. 994509 is represented by the following chemical structure:

Structure 1. Compound No. 994509

In certain embodiments, the sodium salt of Compound No. 994509 is represented by the following chemical structure:

Structure 2. The sodium salt of Compound No. 994509

2. Compound No. 1040500

In certain embodiments, Compound No. 1040500 is characterized as a 5-10-5 MOE gapmer having a sequence of (from 5′ to 3′) GCTTCTCAAATCAGGTGTAC (SEQ ID NO: 1045), wherein each of (nucleosides 1-5 and 16-20 (from 5′ to 3′) are 2′-MOE nucleosides and each of nucleosides 6-15 are 2′-β-D-deoxynucleosides, wherein the internucleoside linkages between nucleosides 2 to 3, 3 to 4, 4 to 5, 16 to 17, and 17 to 18 are phosphodiester internucleoside linkages and the internucleoside linkages between nucleosides 1 to 2, 5 to 6, 6 to 7, 7 to 8, 8 to 9, 9 to 10, 10 to 11, 11 to 12, 12 to 13, 13 to 14, 14 to 15, 15 to 16, 18 to 19, and 19 to 20 are phosphorothioate internucleoside linkages, and wherein each cytosine is a 5-methyl cytosine.

In certain embodiments, Compound No. 1040500 is represented by the following chemical notation (5′ to 3′): Ges ^(m)Ceo Teo Teo ^(m)Ces Tds ^(m)Cds Ads Ads Ads Tds ^(m)Cds Ads Gds Gds Teo Geo Tes Aes ^(m)Ce (SEQ ID NO: 1045), wherein,

A=an adenine nucleobase,

^(m)C=a 5-methyl cytosine nucleobase,

G=a guanine nucleobase,

T=a thymine nucleobase,

e=a 2′-MOE sugar moiety,

d=a 2′-β-D deoxyribosyl sugar moiety,

s=a phosphorothioate internucleoside linkage, and

o=a phosphodiester internucleoside linkage.

In certain embodiments, Compound No. 1040500 is represented by the following chemical structure:

Structure 3. Compound No. 1040500

In certain embodiments, the sodium salt of Compound No. 1040500 is represented by the following chemical structure:

Structure 4. The sodium salt of Compound No. 1040500

3. Compound No. 1041927

In certain embodiments, Compound No. 1041927 is characterized as a 5-10-5 MOE gapmer having a sequence of (from 5′ to 3′) GCCTTTATAACTTTTCTTTC (SEQ ID NO: 2552), wherein each of nucleosides 1-5 and 16-20 (from 5′ to 3′) are 2′-MOE nucleosides and each of nucleosides 6-15 are 2′-β-D-deoxynucleosides, wherein the internucleoside linkages between nucleosides 2 to 3, 3 to 4, 4 to 5, 16 to 17, and 17 to 18 are phosphodiester internucleoside linkages and the internucleoside linkages between nucleosides 1 to 2, 5 to 6, 6 to 7, 7 to 8, 8 to 9, 9 to 10, 10 to 11, 11 to 12, 12 to 13, 13 to 14, 14 to 15, 15 to 16, 18 to 19, and 19 to 20 are phosphorothioate internucleoside linkages, and wherein each cytosine is a 5-methyl cytosine.

In certain embodiments, Compound No. 1041927 is represented by the following chemical notation (5′ to 3′): Ges ^(m)Ceo ^(m)Ceo Teo Tes Tds Ads Tds Ads Ads ^(m)Cds Tds Tds Tds Tds ^(m)Ceo Teo Tes Tes ^(m)Ce (SEQ ID NO: 2552), wherein,

A=an adenine nucleobase,

^(m)C=a 5-methyl cytosine nucleobase,

G=a guanine nucleobase,

T=a thymine nucleobase,

e=a 2′-MOE sugar moiety,

d=a 2′-β-D deoxyribosyl sugar moiety,

s=a phosphorothioate internucleoside linkage, and

o=a phosphodiester internucleoside linkage.

In certain embodiments, Compound No. 1041927 is represented by the following chemical structure:

Structure 5. Compound No. 1041927

In certain embodiments, the sodium salt of Compound No. 1041927 is represented by the following chemical structure:

Structure 6. The Sodium Salt of Compound No. 1041927

4. Compound No. 1055001

In certain embodiments, Compound No. 1055001 is characterized as a 5-10-5 MOE gapmer having a sequence of (from 5′ to 3′) TTCAGTTTAGTTGCAGCCAT (SEQ ID NO: 3190), wherein each of nucleosides 1-5 and 16-20 (from 5′ to 3′) are 2′-MOE nucleosides and each of nucleosides 6-15 are 2′-β-D-deoxynucleosides, wherein the internucleoside linkages between nucleosides 2 to 3, 3 to 4, 4 to 5, 16 to 17, and 17 to 18 are phosphodiester internucleoside linkages and the internucleoside linkages between nucleosides 1 to 2, 5 to 6, 6 to 7, 7 to 8, 8 to 9, 9 to 10, 10 to 11, 11 to 12, 12 to 13, 13 to 14, 14 to 15, 15 to 16, 18 to 19, and 19 to 20 are phosphorothioate internucleoside linkages, and wherein each cytosine is a 5-methyl cytosine.

In certain embodiments, Compound No. 1055001 is represented by the following chemical notation (5′ to 3′): Tes Teo ^(m)Ceo Aeo Ges Tds Tds Tds Ads Gds Tds Tds Gds ^(m)Cds Ads Geo ^(m)Ceo ^(m)Ces Aes Te (SEQ ID NO: 3190), wherein,

A=an adenine nucleobase,

^(m)C=a 5-methyl cytosine nucleobase,

G=a guanine nucleobase,

T=a thymine nucleobase,

e=a 2′-MOE sugar moiety,

d=a 2′-β-D deoxyribosyl sugar moiety,

s=a phosphorothioate internucleoside linkage, and

o=a phosphodiester internucleoside linkage.

In certain embodiments, Compound No. 1055001 is represented by the following chemical structure:

Structure 7. Compound No. 1055001

In certain embodiments, the sodium salt of Compound No. 1055001 is represented by the following chemical structure:

Structure 8. The Sodium Salt of Compound No. 1055001

5. Compound No. 1371311

In certain embodiments, Compound No. 1371311 is characterized as a 5-10-5 MOE gapmer having a sequence of (from 5′ to 3′) CCCGTA TTCCTCTTA CCATC (SEQ ID NO: 3590), wherein each of nucleosides 1-5 and 16-20 (from 5′ to 3′) are 2′-MOE nucleosides and each of nucleosides 6-15 are 2′-β-D-deoxynucleosides, wherein the internucleoside linkages between nucleosides 2 to 3, 3 to 4, 4 to 5, 16 to 17, and 17 to 18 are phosphodiester internucleoside linkages and the internucleoside linkages between nucleosides 1 to 2, 5 to 6, 6 to 7, 7 to 8, 8 to 9, 9 to 10, 10 to 11, 11 to 12, 12 to 13, 13 to 14, 14 to 15, 15 to 16, 18 to 19, and 19 to 20 are phosphorothioate internucleoside linkages, and wherein each cytosine is a 5-methyl cytosine.

In certain embodiments, Compound No. 1371311 is represented by the following chemical notation (5′ to 3′): ^(m)Ces ^(m)Ceo ^(m)Ceo Geo Tes Ads Tds Tds ^(m)Cds ^(m)Cds Tds ^(m)Cds Tds Tds Ads ^(m)Ceo ^(m)Ceo Aes Tes ^(m)Ce (SEQ ID NO: 3590), wherein,

A=an adenine nucleobase,

^(m)C=a 5-methyl cytosine nucleobase,

G=a guanine nucleobase,

T=a thymine nucleobase,

e=a 2′-MOE sugar moiety,

d=a 2′-β-D deoxyribosyl sugar moiety,

s=a phosphorothioate internucleoside linkage, and

o=a phosphodiester internucleoside linkage.

In certain embodiments, Compound No. 1371311 is represented by the following chemical structure:

Structure 9. Compound No. 1371311

In certain embodiments, the sodium salt of Compound No. 1371311 is represented by the following chemical structure:

Structure 10. The Sodium Salt of Compound No. 1371311

6. Compound No. 1385293

In certain embodiments, Compound No. 1385293 is characterized as a 5-8-4 MOE gapmer having a sequence of (from 5′ to 3′) TCAGTTTAGTTGCAGCC (SEQ TD NO: 3638), wherein each of nucleosides 1-5 and 14-17 (from 5′ to 3′) are 2′-MOE nucleosides and each of nucleosides 6-13 are 2′-β-D-deoxynucleosides, wherein the internucleoside linkages between nucleosides 4 to 5 and 14 to 15 are phosphodiester internucleoside linkages and the internucleoside linkages between nucleosides to 2, 3 to 4, 5 to 6, 6 to 7, 7 to 8, 8 to 9, 9 to 10, 10 to 11, 11 to 12, 12 to 13, 13 to 14, 15 to 16, and 16 to 17 are phosphorothioate internucleoside linkages, and wherein each cytosine is a 5-methyl cytosine.

In certain embodiments, Compound No. 1385293 is represented by the following chemical notation (5′ to 3′): Tes ^(m)Ces Aes Geo Tes Tds Tds Ads Gds Tds Tds Gds ^(m)Cds Aeo Ges ^(m)Ces ^(m)Ce (SEQ ID NO: 3638), wherein,

A=an adenine nucleobase,

^(m)C=a 5-methyl cytosine nucleobase,

G=a guanine nucleobase,

T=a thymine nucleobase,

e=a 2′-MOE sugar moiety,

d=a 2′-β-D deoxyribosyl sugar moiety,

s=a phosphorothioate internucleoside linkage, and

o=a phosphodiester internucleoside linkage.

In certain embodiments, Compound No. 1385293 is represented by the following chemical structure:

Structure 11. Compound No. 1385293

In certain embodiments, the sodium salt of Compound No. 1385293 is represented by the following chemical structure:

Structure 12. The Sodium Salt of Compound No. 1385293

VIII. Certain Hotspot Regions

In certain embodiments, nucleobases in the ranges specified below comprise a hotspot region of ATXN1 nucleic acid. In certain embodiments, modified oligonucleotides that are complementary within a hotspot region of ATXN1 nucleic acid achieve an average of more than 75% reduction of ATXN1 RNA in vitro in the standard cell assay. In certain embodiments, modified oligonucleotides that are complementary within a hotspot region of ATXN1 nucleic acid achieve an average of 24% or greater reduction of ATXN1 RNA in vivo in the standard in vivo assay. In certain embodiments, modified oligonucleotides that are complementary within a hotspot region of ATXN1 nucleic acid achieve an average of 45% or greater reduction of ATXN1 RNA in vivo in the standard in vivo assay.

1. Nucleobases 5472-5552 of SEQ ID NO: 1 or 459725-459805 of SEQ ID NO: 2

In certain embodiments, nucleobases 5472-5552 of SEQ TD NO: 1 or 459725-459805 of SEQ ID NO: 2 comprise a hotspot region. In certain embodiments, modified oligonucleotides are complementary within nucleobases 5472-5552 of SEQ TD NO: 1 or 459725-459805 of SEQ TD NO: 2. In certain embodiments, modified oligonucleotides are 20 nucleobases in length. In certain embodiments, modified oligonucleotides are 17 nucleobases in length. In certain embodiments, modified oligonucleotides are gapmers. In certain embodiments, modified oligonucleotides are mixed wing gapmers.

In certain embodiments, the gapmers are 5-10-5 MOE gapmers. In certain embodiments, the gapmers are 6-10-4 MOE gapmers. In certain embodiments, the gapmers are 5-8-4 MOE gapmers or 5-8-4 mixed MOE/cEt gapmers. In certain embodiments, the mixed wing gapmers have the sugar motif in order from 5′ to 3′: eeeeeddddddddkkee; wherein ‘d’ represents a 2′-β-D-deoxyribosyl sugar moiety, ‘k’ represents a cEt sugar moiety, and ‘e’ represents a 2′-MOE sugar moiety. In certain embodiments, the gapmers comprise a 2′-substituted nucleoside in the gap. In certain embodiments, the 2′-substituted nucleoside comprises a 2′-OMe sugar moiety. In certain embodiments, the 2′-substituted nucleoside is at position 2 of the gap (5′ to 3′). In certain embodiments, the gapmers have the sugar motif in order from 5′ to 3′: eeeeedyddddddddeeeee or eeeeedyddddddkkee; wherein ‘d’ represents a 2′-β-D-deoxyribosyl sugar moiety, ‘k’ represents a cEt sugar moiety, ‘e’ represents a 2′-MOE sugar moiety, and “y” represents a 2′-OMe sugar moiety. In certain embodiments, the internucleoside linkages of the modified oligonucleotides are phosphorothioate internucleoside linkages and phosphodiester internucleoside linkages. In certain embodiments, the phosphodiester (“o”) and phosphorothioate (“s”) internucleoside linkages are arranged in order from 5′ to 3′: In certain embodiments, modified nucleotides have an internucleoside linkage motif of sooosssssssssssooss, sssosssssssssssosss, sssosssssssssoss, or sooooossssssssssoss wherein each “s” represents a phosphorothioate internucleoside linkage and each “o” represents a phosphodiester internucleoside linkage.

The nucleobase sequences of SEQ ID Nos: 196, 274, 352, 430, 508, 2578, 2655, 2732, 2809, 2886, 2963, 3121, 3122, 3190, 3191, 3192, 3262, 3330, 3331, 3332, 3401, 3402, 3575, 3577, 3620, 3624, 3638-3640, 3653-3655, 3662, 3665, and 3669 are complementary within nucleobases 5472-5552 of SEQ ID NO: 1 or 459725-459805 of SEQ ID NO: 2.

The nucleobase sequence of Compound Nos.: 994446-994450, 1040296-1040301, 1055001-1055011, 1342062, 1342063, 1342067, 1342068, 1365271, 1365272, 1365274, 1365294, 1365299, 1365300, 1371818, 1371821, 1371827, 1371829, 1371837, 1371843, 1371866, 1371869, 1371871, 1371876, 1385293, 1394156-1394160, 1394162, 1394164, 1394166-1394168, 1394533, 1394544, 1394546, 1394549, and 1394553 are complementary within nucleobases 5472-5552 of SEQ ID NO: 1 or 459725-459805 of SEQ ID NO: 2.

In certain embodiments, modified oligonucleotides complementary within nucleobases 5472-5552 of SEQ ID NO: 1 or 459725-459805 of SEQ ID NO: 2 achieve at least 58% reduction of ATXN1 RNA in vitro in the standard cell assay. In certain embodiments, modified oligonucleotides complementary within nucleobases 5472-5552 of SEQ ID NO: 1 or 459725-459805 of SEQ ID NO: 2 achieve an average of 90% reduction of ATXN1 RNA in vitro in the standard cell assay. In certain embodiments, modified oligonucleotides complementary within nucleobases 5472-5552 of SEQ ID NO: 1 or 459725-459805 of SEQ ID NO: 2 achieve an average of 52% reduction of ATXN1 RNA in vivo in the standard in vivo assay.

2. Nucleobases 5906-6005 of SEQ ID NO: 1 or 460159-460258 of SEQ ID NO: 2

In certain embodiments, nucleobases 5906-6005 of SEQ ID NO: 1 or 460159-460258 of SEQ ID NO: 2 comprise a hotspot region. In certain embodiments, modified oligonucleotides are complementary to nucleobases 5906-6005 of SEQ ID NO: 1 or 460159-460258 of SEQ ID NO: 2. In certain embodiments, modified oligonucleotides are 20 nucleobases in length. In certain embodiments, modified oligonucleotides are 17 nucleobases in length. In certain embodiments, modified oligonucleotides are mixed wing gapmers.

In certain embodiments, the gapmers are 5-10-5 MOE gapmers. In certain embodiments, the gapmers are 6-10-4 MOE gapmers. In certain embodiments, the gapmers are 5-8-4 MOE gapmers or 5-8-4 mixed MOE/cEt gapmers. In certain embodiments, the mixed wing gapmers have the sugar motif in order from 5′ to 3′: eeeeeddddddddkkee; wherein ‘d’ represents a 2′-β-D-deoxyribosyl sugar moiety, ‘k’ represents a cEt sugar moiety, and ‘e’ represents a 2′-MOE sugar moiety.

In certain embodiments, the internucleoside linkages of the modified oligonucleotides are phosphorothioate internucleoside linkages and phosphodiester internucleoside linkages. In certain embodiments, the phosphodiester (“o”) and phosphorothioate (“s”) internucleoside linkages are arranged in order from 5′ to 3′: In certain embodiments, modified nucleotides have an internucleoside linkage motif of sooosssssssssssooss, sssosssssssssssosss, sssosssssssssoss, or sooooossssssssssoss wherein each “s” represents a phosphorothioate internucleoside linkage and each “o” represents a phosphodiester internucleoside linkage.

The nucleobase sequences of SEQ ID Nos: 42, 120, 198, 276, 509, 587, 2502, 2579, 2656, 2733, 2810, 2887, 2964, 3585, 3588-3590, 3615, 3618, 3622, 3657, 3660, 3661, 3663, 3664, and 3666-3668 are complementary within nucleobases 5906-6005 of SEQ ID NO: 1 or 460159-460258 of SEQ ID NO: 2.

The nucleobase sequence of Compound Nos.: 994458-994463, 1040327-1040333, 1367569, 1367580-1367581, 1367589-1367591, 1371311, 1371820, 1371823, 1371825, 1371842, 1371865, 1371868, 1371870, 1371873, 1371875, 1371877, 1394161, 1394163, 1394165, 1394524, 1394538, 1394541, 1394543, 1394545, 1394548, and 1394550-1394552 are complementary within nucleobases 5906-6005 of SEQ ID NO: 1 or 460159-460258 of SEQ ID NO: 2.

In certain embodiments, modified oligonucleotides complementary within 5906-6005 of SEQ ID NO: 1 or 460159-460258 of SEQ ID NO: 2 achieve at least 26% reduction of ATXN1 RNA in vitro in the standard cell assay. In certain embodiments, modified oligonucleotides complementary within nucleobases 5906-6005 of SEQ ID NO: 1 or 460159-460258 of SEQ ID NO: 2 achieve an average of 78% reduction of ATXN1 RNA in vitro in the standard cell assay. In certain embodiments, modified oligonucleotides complementary within nucleobases 5906-6005 of SEQ ID NO: 1 or 460159-460258 of SEQ ID NO: 2 achieve an average of 51% reduction of ATXN1 RNA in vivo in the standard in vivo assay.

3. Nucleobases 7868-7911 of SEQ ID NO: 1 or 462121-462164 of SEQ ID NO: 2

In certain embodiments, nucleobases 7868-7911 of SEQ ID NO: 1 or 462121-462164 of SEQ ID NO: 2 comprise a hotspot region. In certain embodiments, modified oligonucleotides are complementary to nucleobases 7868-7911 of SEQ ID NO: 1 or 462121-462164 of SEQ ID NO: 2. In certain embodiments, modified oligonucleotides are 20 nucleobases in length. In certain embodiments, modified oligonucleotides are gapmers.

In certain embodiments, the gapmers are 5-10-5 MOE gapmers. In certain embodiments, the gapmers are 6-10-4 MOE gapmers.

In certain embodiments, the internucleoside linkages of the modified oligonucleotides are phosphorothioate internucleoside linkages and phosphodiester internucleoside linkages. In certain embodiments, the phosphodiester (“o”) and phosphorothioate (“s”) internucleoside linkages are arranged in order from 5′ to 3′: In certain embodiments, modified nucleotides have an internucleoside linkage motif of sooosssssssssssooss, sssosssssssssssosss, or sooooossssssssssoss wherein each “s” represents a phosphorothioate internucleoside linkage and each “o” represents a phosphodiester internucleoside linkage.

The nucleobase sequences of SEQ ID Nos: 48, 126, 2044, and 2121 are complementary within nucleobases 7868-7911 of SEQ ID NO: 1 or 462121-462164 of SEQ ID NO: 2.

The nucleobase sequence of Compound Nos.: 994508, 994509, 1040499, 1040450, 1394513, and 1394529 are complementary within nucleobases 7868-7911 of SEQ ID NO: 1 or 462121-462164 of SEQ ID NO: 2.

In certain embodiments, modified oligonucleotides complementary within 7868-7911 of SEQ ID NO: 1 or 462121-462145 of SEQ ID NO: 2 achieve at least 61% reduction of ATXN1 RNA in vitro in the standard cell assay. In certain embodiments, modified oligonucleotides complementary within nucleobases 7868-7911 of SEQ ID NO: 1 or 462121-462145 of SEQ ID NO: 2 an average of 79% reduction of ATXN1 RNA in vitro in the standard cell assay. In certain embodiments, modified oligonucleotides complementary within nucleobases 7868-7911 of SEQ ID NO: 1 or 462121-462164 of SEQ ID NO: 2 achieve an average of 53% reduction of ATXN1 RNA in vivo in the standard in vivo assay.

4. Nucleobases 8481-8514 of SEQ ID NO: 1 or 462734-462767 of SEQ ID NO: 2

In certain embodiments, nucleobases 8481-8514 of SEQ ID NO: 1 or 462734-462767 of SEQ ID NO: 2 comprise a hotspot region. In certain embodiments, modified oligonucleotides are complementary to nucleobases 8481-8514 of SEQ ID NO: 1 or 462734-462767 of SEQ ID NO: 2. In certain embodiments, modified oligonucleotides are 20 nucleobases in length. In certain embodiments, modified oligonucleotides are gapmers.

In certain embodiments, the gapmers are 5-10-5 MOE gapmers. In certain embodiments, the gapmers are 6-10-4 MOE gapmers.

In certain embodiments, the internucleoside linkages of the modified oligonucleotides are phosphorothioate internucleoside linkages and phosphodiester internucleoside linkages. In certain embodiments, the phosphodiester (“o”) and phosphorothioate (“s”) internucleoside linkages are arranged in order from 5′ to 3′: In certain embodiments, modified nucleotides have an internucleoside linkage motif of sooosssssssssssooss, sssosssssssssssosss, or sooooossssssssssoss wherein each “s” represents a phosphorothioate internucleoside linkage and each “o” represents a phosphodiester internucleoside linkage.

The nucleobase sequences of SEQ ID Nos: 128, 206, 284, 1045, 1122, 1199, and 1276 are complementary within nucleobases 8481-8514 of SEQ ID NO: 1 or 462734-462767 of SEQ ID NO: 2.

The nucleobase sequence of Compound Nos.: 994525-994527, 1040500-1040503, 1394514, and 1394525 are complementary within nucleobases 8481-8514 of SEQ ID NO: 1 or 462734-462767 of SEQ ID NO: 2.

In certain embodiments, modified oligonucleotides complementary within 8481-8514 of SEQ ID NO: 1 or 462734-462767 of SEQ ID NO: 2 achieve at least 54% reduction of ATXN1 RNA in vitro in the standard cell assay. In certain embodiments, modified oligonucleotides complementary within nucleobases 8481-8514 of SEQ ID NO: 1 or 462734-462767 of SEQ ID NO: 2 achieve an average of 79% reduction of ATXN1 RNA in vitro in the standard cell assay. In certain embodiments, modified oligonucleotides complementary within nucleobases 8481-8514 of SEQ ID NO: 1 or 462734-462767 of SEQ ID NO: 2 achieve an average of 48% reduction of ATXN1 RNA in vivo in the standard in vivo assay.

5. Nucleobases 446679-446706 of SEQ ID NO: 2

In certain embodiments, nucleobases 446679-446706 of SEQ ID NO: 2 comprise a hotspot region. In certain embodiments, modified oligonucleotides are complementary to nucleobases 446679-446706 of SEQ ID NO: 2. In certain embodiments, modified oligonucleotides are 20 nucleobases in length. In certain embodiments, modified oligonucleotides are gapmers.

In certain embodiments, the gapmers are 5-10-5 MOE gapmers. In certain embodiments, the gapmers are 6-10-4 MOE gapmers.

In certain embodiments, 446679-446706 of SEQ ID NO: 2 comprise a hotspot region. In certain embodiments, modified oligonucleotides are complementary within 446679-446706 of SEQ ID NO: 2. In certain embodiments, modified oligonucleotides are 20 nucleobases in length. In certain embodiments, modified oligonucleotides are 17 nucleobases in length. In certain embodiments, modified oligonucleotides are gapmers. In certain embodiments, the gapmers are MOE gapmers. In certain embodiments, the internucleoside linkages of the modified oligonucleotides are phosphorothioate internucleoside linkages and phosphodiester internucleoside linkages. In certain embodiments, the phosphodiester (“o”) and phosphorothioate (“s”) internucleoside linkages are arranged in order from 5′ to 3′: In certain embodiments, modified nucleotides have an internucleoside linkage motif of sooosssssssssssooss, sssosssssssssssosss, or sooooossssssssssoss wherein each “s” represents a phosphorothioate internucleoside linkage and each “o” represents a phosphodiester internucleoside linkage.

The nucleobase sequences of SEQ ID Nos: 2475, 2552, 2629, 2706, 2783, 3627-3630, and 3644 are complementary within nucleobases 446679-446706 of SEQ ID NO: 2.

The nucleobase sequence of Compound Nos.: 1041926-1041930, 1364282, 1365258-1365261, 1365282-1365284, 1365287, and 1394522 are complementary within nucleobases 446679-446706 of SEQ ID NO: 2.

In certain embodiments, modified oligonucleotides complementary within nucleobases 446679-446706 of SEQ ID NO: 2 achieve at least 67% reduction of ATXN1 RNA in vitro in the standard cell assay. In certain embodiments, modified oligonucleotides complementary within nucleobases 446679-446706 of SEQ ID NO: 2.achieve an average of 81% reduction of ATXN1 RNA in vitro in the standard cell assay.

6. Additional Hotspot Regions

In certain embodiments, the ranges described in the Table below comprise hotspot regions. Each hotspot region begins with the nucleobase of SEQ ID NO:1 identified in the “Start Site SEQ ID NO: 1” column and ends with the nucleobase of SEQ ID NO: 1 identified in the “Stop Site SEQ ID NO: 1” column. In certain embodiments, modified oligonucleotides are complementary within any of the hotspot regions 1-53, as defined in the table below. In certain embodiments, modified oligonucleotides are 17 nucleobases in length. In certain embodiments, modified oligonucleotides are 20 nucleobases in length.

In certain embodiments, the gapmers are 5-10-5 MOE gapmers. In certain embodiments, the gapmers are 6-10-4 MOE gapmers. In certain embodiments, the gapmers are 5-8-4 MOE gapmers or 5-8-4 mixed MOE/cEt gapmers. In certain embodiments, the mixed wing gapmers have the sugar motif in order from 5′ to 3′: eeeeeddddddddkkee; wherein ‘d’ represents a 2′-β-D-deoxyribosyl sugar moiety, ‘k’ represents a cEt sugar moiety, and ‘e’ represents a 2′-MOE sugar moiety. In certain embodiments, gapmers comprise a 2′-substituted nucleoside in the gap. In certain embodiments, the 2′-substituted nucleoside comprises a 2′-OMe sugar moiety. In certain embodiments, the 2′-substituted nucleoside is at position 2 of the gap (5′ to 3′). In certain embodiments, the gapmers have the sugar motif in order from 5′ to 3′: eeeeedyddddddddeeeee or eeeeedyddddddkkee; wherein ‘d’ represents a 2′-β-D-deoxyribosyl sugar moiety, ‘k’ represents a cEt sugar moiety, ‘e’ represents a 2′-MOE sugar moiety, and “y” represents a 2′-OMe sugar moiety.

In certain embodiments, the internucleoside linkages of the modified oligonucleotides are phosphorothioate internucleoside linkages and phosphodiester internucleoside linkages. In certain embodiments, the phosphodiester (“o”) and phosphorothioate (“s”) internucleoside linkages are arranged in order from 5′ to 3′: In certain embodiments, modified nucleotides have an internucleoside linkage motif of sooosssssssssssooss, sssosssssssssssosss, sssosssssssssoss, or sooooossssssssssoss wherein each “s” represents a phosphorothioate internucleoside linkage and each “o” represents a phosphodiester internucleoside linkage.

The nucleobase sequence of compounds listed in the “Compound No. in range” column in the table below are complementary to SEQ ID NO: 2 within the specified hotspot region. The nucleobase sequence of the oligonucleotides listed in the “SEQ ID NO: in range” column in the table below are complementary to the target sequence, SEQ ID NO: 2, within the specified hotspot region.

In certain embodiments, modified oligonucleotides complementary to nucleobases within the hotspot region achieve at least “Min.% Red. in vitro” (minimum % reduction, relative to untreated control cells) of ATXN1 RNA in vitro in the standard cell assay, as indicated in the table below. In certain embodiments, modified oligonucleotides complementary to nucleobases within the hotspot region achieve an average of “Avg.% Red. in vitro” (average % reduction, relative to untreated control cells) of ATXN1 RNA in vitro in the standard cell assay, as indicated in the table below. In certain embodiments, modified oligonucleotides complementary to nucleobases within the hotspot region achieve a maximum of “Max. % Red. in vitro” (maximum % reduction, relative to untreated control cells) of ATXN1 RNA in vitro in the standard cell assay, as indicated in the table below. In certain embodiments, modified oligonucleotides complementary to nucleobases within the hotspot region achieve an average of “Avg. % Red. in vivo” (average % reduction, relative to PBS-treated animals) of ATXN1 RNA in vivo in the standard in vivo assay in cortical tissue, as indicated in the table below. Note that due to the transgenic mouse model used, only compounds targeting nucleosides 435531-464889 of SEQ ID NO: 2 were tested in vivo; “n.d.” indicates that no in vivo data are available for compounds within that range. In other cases, average reduction in vivo includes a subset of the compounds in any given hotspot, as not all compounds were tested in vivo.

TABLE 1 ATXN1 Hotspots Avg. SEQ SEQ SEQ SEQ Min. Max. Avg. % ID ID ID ID % % % Red. Hot NO: 1 NO: 1 NO: 2 NO: 2 Red. Red. Red. in spot Start Stop Start Stop in in in vivo Compound No. SEQ ID NO in ID Site Site Site Site vitro vitro vitro (ctx) in range range  1 5477 5552 459730 459805 58 96 90 54 994446-994450, 196, 274, 352, 1040296-1040301, 430, 508, 1055001-1055011, 2578, 2655, 1342062, 1342067, 2732, 2809, 1365271, 1365272, 2886, 2963, 1365274, 1365294, 3121, 3122, 1365299-1365300, 3190-3192, 1371818, 1371827, 3262, 3330- 1371829, 1371837, 3332, 3401, 1371843, 1371871, 3402, 3575, 1371876, 1385293, 3577, 3620, 1394156-1394160, 3624, 3638- 1394162, 1394164, 3640, 3653- 1394166-1394168, 3655, 3662, 1394533, 1394544, 3665, 3669 1394546, 1394549, 1394553  2 5906 6005 460159 460258 26 97 78 51 994458-994463, 42, 120, 198, 1040327-1040333, 276, 509, 587, 1367569, 1367580- 2502, 2579, 1367581, 1367589- 2656, 2733, 1367591, 1371311, 2810, 2887, 1371820, 1371823, 2964, 3585, 1371825, 1371842, 3588-3590, 1371865, 1371868, 3615, 3618, 1371870, 1371873, 3622, 3657, 1371875, 1371877, 3660, 3661, 1394161, 1394163, 3663, 3664, 1394165, 1394524, 3666-3668 1394538, 1394541, 1394543, 1394545, 1394548, 1394550- 1394552  3 7868 7911 462121 462145 61 94 79 53 994508, 994509, 48, 126, 2044, 1040499, 1040450, 2121 1394513, 1394529  4 8481 8514 462734 462767 54 89 79 48 994525-994527, 128, 206, 284, 1040500-1040503, 1045, 1122, 1394514, 1394525 1199, 1276  5 N/A N/A 446679 446706 67 89 81 24 1041926-1041930, 2475, 2552, 1364282, 1365258- 2629, 2706, 1365261, 1365282- 2783, 3627- 1365284, 1365287, 3630, 3644 1394522  6 99 140 2609 2650 43 90 76 n.d. 994310-994313, 179, 257, 335, 1054946-1054957 413, 3111- 3113, 3183, 3253-3254, 3321-3322, 3394-3395, 3464-3465  7 195 227 9911 9943 64 92 78 n.d. 994597-994601, 137, 215, 293, 1055055-1055061 371, 449, 3131-3132, 3201, 3341- 3342, 3410, 3478  8 243 275 10654 10686 75 93 85 n.d. 994314, 1054962- 491, 3114, 1054971 3184-3185, 3255-3256, 3323-3324, 3396, 3466- 3467  9 413 454 106155 106196 68 95 86 n.d. 994318-994324 25, 180, 258, 336, 414, 492, 570 10 500 589 178110 178199 60 98 88 n.d. 994325-994328, 103, 181, 259, 1054972-1054984 337, 3115- 3117, 3186- 3187, 3257- 3258, 3325- 3326, 3397- 3398, 3468- 3469 11 587 619 N/A N/A 80 99 94 n.d. 994329, 1054990- 415, 3119, 1054999 3188-3189, 3260-3261, 3328-3329, 3400, 3471- 3472 12 3984 4031 458237 458284 77 95 83 24 994408-994409, 347, 425, 1040170-1040173 2728, 2805, 2882, 2959, 3036 13 4434 4457 458687 458710 88* 88* 88* 49 994419, 1342032, 582, 3563, 1364280, 1365267, 3593, 3605, 1365268, 1365270, 3621, 3635- 1365290-1365292, 3637, 3648- 1365298, 1371322, 3649, 3652, 1371325, 1371809, 3656, 3658- 1371824, 1371851, 3659 1371854, 1371872, 1385295, 1394153- 1394155, 1394534, 1394537, 1394539, 1394540, 1394547 14 4497 4553 458750 458806 48 91 78 25 1040205-1040211 651, 728, 805, 882, 959, 2960, 3037 15 4586 4640 458839 458893 63 99 87 50 994420-994422, 37, 115, 193, 1040212-1040215 1036, 1113, 1190, 1267 16 4725 4786 458978 459039 24 98 77 33 994429-994430, 116, 194, 652, 1040222-1040239, 1806, 1883, 1342061, 1342064, 1960, 2037, 1342069, 1342071, 2114, 2191, 1342074-1342076, 2268, 2345, 1364283, 1365262- 2422, 2499, 1356265, 1365285- 2576, 2653, 1365286, 1365288- 2730, 2807, 1365289, 1371808, 2884, 2961, 1371810, 1371813, 3038, 3558, 1371815-1371816, 3560-3562, 1371819, 1371822, 3574, 3576, 1371844-1371845, 3578, 3592, 1371848, 1371853, 3594, 3597, 1385294, 1394507, 3604, 3631- 1394511, 1394518, 3635, 3645, 1394523, 1394527 3646-3647 17 6015 6099 460268 460352 58 94 78 34 994464-994469, 43, 121, 354, 1040334-1040344, 1432, 510, 588, 1055012-1055023, 655, 732, 809, 1342039, 1342041, 886, 963, 1342044, 1342046, 1040, 1117, 1342048 1194, 1271, 1348, 3041, 3123-3125, 3193-3194, 3263-3264, 3333-3334, 3403, 3473- 3474, 3541, 3543, 3545, 3565, 3569 18 6919 6960 461172 461213 90 96 93 50 994484, 1040382- 45, 1811, 1040384 1888, 1965 19 7076 7114 461329 461367 76 98 89 58 994490-994496, 46, 124, 202, 1040393-1040395, 280, 358, 513, 1394166-1394167, 591, 2658, 1394516, 1394530 2735, 2812 20 7696 7741 461949 461994 74 94 87 29 994506, 1040435- 515, 966, 1040438 1043, 1120, 1197 21 8194 8257 462447 462510 58 97 82 37 994516-994521, 49, 127, 205, 1040472-1040482, 283, 361, 439, 1394512, 1394517, 1352, 1429, 1394528, 1394531 1506, 1583, 1660, 1737, 1814, 1891, 1968, 2045, 2122 22 9181 9214 463434 463467 68 97 82 51 994549-994551, 131, 209, 287, 1040566-1040567 1201, 1278 23 9472 9513 463725 463766 79 91 84 25 994559-994561, 288, 366, 444, 1055024-1055036 3126-3127, 3195-3197, 3265-3266, 3335-3336, 3404-3405, 3475-3476 24 9667 9730 463920 463983 75 94 86 35 994562-994564, 55, 522, 600, 1040612-1040613 2280, 2357 25 10095 10121 464348 464374 66 95 84 13 994571, 1055043- 601, 3129, 1055048 3199, 3268, 3339, 3407, 3408 26 10133 10158 464386 464411 84 92 88 n.d. 994572-994574, 56, 134, 212, 1040633 1434 27 10237 10277 464490 464530 72 90 82 n.d. 994579-994580, 57, 602, 665, 1040653-1040658 742, 819, 896, 2974, 3051 28 10311 10353 464564 464606 80 95 89 n.d. 994581-994583 135, 213, 291, 1040663-1040666 1281, 1358, 1435, 1512 29 N/A N/A 439072 439126 69 99 87 47 994809-994811, 475, 553, 631, 1041407-1041414, 1920, 1997, 1364281, 1365254- 2074, 2151, 1365255, 1365278, 2228, 2305, 1365281, 1394526 2382, 2459, 3625-3626, 3642-3643 30 N/A N/A 17722 17748 72 99 87 n.d. 994605, 1055065- 138, 3134, 1055071 3202-3203, 3270, 3343, 3412, 3480 31 N/A N/A 85512 85545 64 92 76 n.d. 994630, 1055084- 219, 3137, 1055094 3206-3207, 3273-3274, 3346-3347, 3415-3416, 3483-3484 32 N/A N/A 179779 179809 43 96 81 n.d. 994690, 1055106- 538, 3140, 1055113 3210, 3276- 3277, 3350, 3419-3420, 3487 33 N/A N/A 184181 184213 85 99 94 n.d. 994693, 1055123- 149, 3143, 1055132 3212-3213, 3280, 3352- 3353, 3422- 3423, 3490- 3491 34 N/A N/A 203033 203066 48 94 76 n.d. 994700, 1055137- 72, 3144- 1055147 3145, 3214- 3215, 3282- 3283, 3355- 3356, 3425, 3493-3494 35 N/A N/A 203889 203914 81 98 92 n.d. 994701, 1055151- 150, 3147, 1055156 3285, 3357- 3358, 3426, 3495 36 N/A N/A 210720 210755 47 96 80 n.d. 994702, 1055157- 228, 3148- 1055168 3149, 3217- 3218, 3286- 3287, 3359- 3360, 3427- 3429, 3496 37 N/A N/A 212027 212056 69 90 80 n.d. 994703, 1055174- 306, 3151- 1055182 3152, 3220- 3221, 3362, 3430-3431, 3498-3499 38 N/A N/A 217274 217309 40 97 73 n.d. 994706, 1055186- 540, 3153, 1055197 3222-3223, 3290-3291, 3364-3365, 3433-3434, 3500-3502 39 N/A N/A 226995 227019 75 90 81 n.d. 994713, 1055208- 463, 3156, 1055212 3226, 3294, 3368, 3436 40 N/A N/A 251500 251533 68 94 83 n.d. 994717, 1055224- 152, 3159- 1055234 3160, 3229, 3297-3298, 3370-3371, 3439-3440, 3506-3507 41 N/A N/A 284223 284260 96 99 98 n.d. 994731, 1055240- 621, 3162, 1055252 3163, 3231, 3232, 3299, 3300, 3374, 3375, 3442, 3443, 3509, 3510 42 N/A N/A 284331 284370 39 98 88 n.d. 994732, 1055253- 76, 3164- 1055266 3166, 3233- 3234, 3301- 3302. 3376- 3377, 3444- 3446, 3511- 3512 43 N/A N/A 291004 291043 93 99 97 n.d. 994734, 1055268- 232, 3167- 1055281 3168, 3236- 3237, 3303- 3305, 3378- 3379, 3447- 3449, 3513- 3514 44 N/A N/A 296997 297034 73 99 95 n.d. 994735, 1055283- 310, 3169- 1055295 3170, 3238- 3240, 3306- 3307, 3380- 3381, 3450- 3451, 3516- 3517 45 N/A N/A 306737 306769 78 98 92 n.d. 994740, 1055300- 77, 3171, 1055305 3241, 3309, 3383, 3453, 3519 46 N/A N/A 318484 318519 88 99 96 n.d. 994743, 1041154, 311, 2143, 1055310-1055317 3173-3174, 3243, 3311, 3385, 3454- 3455, 3520 47 N/A N/A 332352 332391 54 99 90 n.d. 994756, 1055321- 79, 3175- 1055334 3177, 3245- 3246, 3313- 3314, 3387- 3388, 3456- 3458, 3521- 3522 48 N/A N/A 347813 347852 57 99 84 n.d. 994761, 1055337- 469, 3178- 1055350 3179, 3248- 3249, 3316- 3317, 3389- 3391, 3459- 3460, 3523- 3525 49 N/A N/A 437786 437815 74 97 91 12 1041316-1041322 2302, 2379, 2456, 2533, 2610, 2687, 2764 50 N/A N/A 439429 439463 81 96 87 14 1041438-1041443, 1844, 1921, 1342051, 1342058, 1998, 2075, 1342043, 1342040 2152, 2229, 3547, 3572 51 N/A N/A 442680 442711 78 93 87 30 1041636-1041639 2312, 2389, 2466, 2543 52 N/A N/A 446727 446761 74 93 84 n.d. 1041936-1041941 782, 859, 936, 1013, 1090, 1167 53 N/A N/A 446925 446970 59 91 77 n.d. 994871-994873, 327, 405, 483, 1041961-1041966 2707, 2784, 2861, 2938, 3015, 3092 54 N/A N/A 451523 451560 82 95 89 n.d. 1042239-1042244 1946, 2023, 2100, 2177, 2254, 2331 55 N/A N/A 451681 451718 72 91 83  0 1042253-1042258 715, 792, 869, 946, 3024, 3101  6 99 140 2609 2650 43 90 76 n.d. 994310-994313, 179, 257, 335, 1054946-1054957 413, 3111- 3113, 3183, 3253-3254, 3321-3322, 3394-3395, 3464-3465 *Only a single compound tested in vitro; see in vivo column for average % reduction. Nonlimiting Disclosure and Incorporation by Reference

Each of the literature and patent publications listed herein is incorporated by reference in its entirety. While certain compounds, compositions and methods described herein have been described with specificity in accordance with certain embodiments, the following examples serve only to illustrate the compounds described herein and are not intended to limit the same. Each of the references, GenBank accession numbers, and the like recited in the present application is incorporated herein by reference in its entirety.

Although the sequence listing accompanying this filing identifies each sequence as either “RNA” or “DNA” as required, in reality, those sequences may be modified with any combination of chemical modifications. One of skill in the art will readily appreciate that such designation as “RNA” or “DNA” to describe modified oligonucleotides is, in certain instances, arbitrary. For example, an oligonucleotide comprising a nucleoside comprising a 2′-OH sugar moiety and a thymine base could be described as a DNA having a modified sugar (2′-OH in place of one 2′-H of DNA) or as an RNA having a modified base (thymine (methylated uracil) in place of an uracil of RNA). Accordingly, nucleic acid sequences provided herein, including, but not limited to those in the sequence listing, are intended to encompass nucleic acids containing any combination of natural or modified RNA and/or DNA, including, but not limited to such nucleic acids having modified nucleobases. By way of further example and without limitation, an oligomeric compound having the nucleobase sequence “ATCGATCG” encompasses any oligomeric compounds having such nucleobase sequence, whether modified or unmodified, including, but not limited to, such compounds comprising RNA bases, such as those having sequence “AUCGAUCG” and those having some DNA bases and some RNA bases such as “AUCGATCG” and oligomeric compounds having other modified nucleobases, such as “AT^(m)CGAUCG,” wherein ^(m)C indicates a cytosine base comprising a methyl group at the 5-position.

Certain compounds described herein (e.g., modified oligonucleotides) have one or more asymmetric center and thus give rise to enantiomers, diastereomers, and other stereoisomeric configurations that may be defined, in terms of absolute stereochemistry, as (R) or (S), as α or β such as for sugar anomers, or as (D) or (L), such as for amino acids, etc. Compounds provided herein that are drawn or described as having certain stereoisomeric configurations include only the indicated compounds. Compounds provided herein that are drawn or described with undefined stereochemistry include all such possible isomers, including their stereorandom and optically pure forms, unless specified otherwise. Likewise, tautomeric forms of the compounds herein are also included unless otherwise indicated. Unless otherwise indicated, compounds described herein are intended to include corresponding salt forms.

The compounds described herein include variations in which one or more atoms are replaced with a non-radioactive isotope or radioactive isotope of the indicated element. For example, compounds herein that comprise hydrogen atoms encompass all possible deuterium substitutions for each of the ¹H hydrogen atoms. Isotopic substitutions encompassed by the compounds herein include but are not limited to: ²H or ³H in place of ¹H, ¹³C or ¹⁴C in place of ¹²C, ¹⁵N in place of ¹⁴N, ¹⁷O or ¹⁸O in place of ¹⁶O, and ³³S, ³⁴S, ³⁵S, or ³⁶S in place of ³²S. In certain embodiments, non-radioactive isotopic substitutions may impart new properties on the oligomeric compound that are beneficial for use as a therapeutic or research tool. In certain embodiments, radioactive isotopic substitutions may make the compound suitable for research or diagnostic purposes such as imaging.

Under certain conditions, certain compounds disclosed herein act as acids. Although such compounds may be drawn or described in protonated (free acid) form, or ionized and in association with a cation (salt) form, aqueous solutions of such compounds exist in equilibrium among such forms. For example, a phosphodiester linkage of an oligonucleotide in aqueous solution exists in equilibrium among free acid, anion and salt forms. Unless otherwise indicated, compounds described herein are intended to include all such forms. Moreover, certain oligonucleotides have several such linkages, each of which is in equilibrium. Thus, oligonucleotides in solution exist in an ensemble of forms at multiple positions all at equilibrium. The term “oligonucleotide” is intended to include all such forms. Drawn structures necessarily depict a single form. Nevertheless, unless otherwise indicated, such drawings are likewise intended to include corresponding forms. Herein, a structure depicting the free acid of a compound followed by the term “or a salt thereof” expressly includes all such forms that may be fully or partially protonated/de-protonated/in association with a cation. In certain instances, one or more specific cation is identified. In certain embodiments, modified oligonucleotides or oligomeric compounds are in aqueous solution with sodium. In certain embodiments, modified oligonucleotides or oligomeric compounds are in aqueous solution with potassium. In certain embodiments, modified oligonucleotides or oligomeric compounds are in PBS. In certain embodiments, modified oligonucleotides or oligomeric compounds are in water. In certain such embodiments, the pH of the solution is adjusted with NaOH and/or HCl to achieve a desired pH.

Herein, certain specific doses are described. A dose may be in the form of a dosage unit. For clarity, a dose (or dosage unit) of a modified oligonucleotide or an oligomeric compound in milligrams indicates the mass of the free acid form of the modified oligonucleotide or oligomeric compound. As described above, in aqueous solution, the free acid is in equilibrium with anionic and salt forms. However, for the purpose of calculating dose, it is assumed that the modified oligonucleotide or oligomeric compound exists as a solvent-free, sodium-acetate free, anhydrous, free acid. For example, where a modified oligonucleotide or an oligomeric compound is in solution comprising sodium (e.g., saline), the modified oligonucleotide or oligomeric compound may be partially or fully de-protonated and in association with Na+ ions. However, the mass of the protons are nevertheless counted toward the weight of the dose, and the mass of the Na+ ions are not counted toward the weight of the dose. Thus, for example, a dose, or dosage unit, of 10 mg of Compound No. 1371311, equals the number of fully protonated molecules that weighs 10 mg. This would be equivalent to 10.59 mg of solvent-free, sodium acetate-free, anhydrous sodiated Compound No. 1371311. When an oligomeric compound comprises a conjugate group, the mass of the conjugate group is included in calculating the dose of such oligomeric compound. If the conjugate group also has an acid, the conjugate group is likewise assumed to be fully protonated for the purpose of calculating dose.

EXAMPLES Example 1: Effect of 5-10-5 MOE Gapmer Modified Oligonucleotides on Human ATXN1 RNA In Vitro, Single Dose

Modified oligonucleotides complementary to human ATXN1 nucleic acid were designed and tested for their single dose effects on ATXN1 mRNA in vitro. The modified oligonucleotides were tested in a series of experiments that had similar culture conditions.

The modified oligonucleotides in the tables below are 5-10-5 MOE gapmers with mixed PO/PS internucleoside linkages. The gapmers are 20 nucleosides in length, wherein the central gap segment consists of ten 2′-β-D-deoxynucleosides and the 3′ and 5′ wings each consist of five 2′-MOE modified nucleosides. The motif for the gapmers is (from 5′ to 3′): eeeeeddddddddddeeeee; wherein “d” represents a 2′-β-D-deoxyribosyl sugar, and ‘e’ represents a 2′-MOE modified ribosyl sugar. The internucleoside linkage motif for the gapmers is (from 5′ to 3′): sooosssssssssssooss; wherein ‘o’ represents a phosphodiester internucleoside linkage and ‘s’ represents a phosphorothioate internucleoside linkage. Each cytosine residue is a 5-methyl cytosine.

“Start site” indicates the 5′-most nucleoside to which the modified oligonucleotide is complementary in the human gene sequence. “Stop site” indicates the 3′-most nucleoside to which the modified oligonucleotide is complementary in the human gene sequence. Each modified oligonucleotide listed in the Tables below is 100% complementary to SEQ ID NO: 1 (GENBANK Accession No. NM_000332.3), or SEQ ID NO: 2 (the complement of GENBANK Accession No. NC_000006.12 truncated from nucleotides 16296001 to 16764000). ‘N/A’ indicates that the modified oligonucleotide is not 100% complementary to that particular gene sequence.

Cultured A-431 cells were treated with modified oligonucleotide at a concentration of 4,000 nM by free uptake at a density of 10,000 cells per well for a treatment period of 48 hours. At the end of their treatment period, total RNA was isolated from the cells and ATXN1 RNA levels were measured by quantitative real-time RTPCR. ATXN1 RNA levels were measured by Human ATXN1 primer probe set RTS37573 (forward sequence CATCCAGAGTGCAGAGATAAGC, designated herein as SEQ ID NO: 11; reverse sequence ACTCTACCAAAACTTCAACGCT, designated herein as SEQ ID NO: 12; probe sequence AGAGGATTGAAGACAGCCATAGCCC, designated herein as SEQ ID NO: 13). ATXN1 RNA levels were normalized to total RNA content, as measured by RIBOGREEN®. Results are presented in the tables below as percent ATXN1 RNA levels relative to untreated control cells (% control). Each table represents results from an individual assay plate. The Compound No. marked with an asterisk (*) indicates that the modified oligonucleotide is complementary to the amplicon region of the primer probe set. Additional assays may be used to measure the potency and efficacy of the modified oligonucleotides complementary to the amplicon region.

TABLE 2  Reduction of ATXN1 RNA by 5-10-5 MOE gapmers with mixed PO/PS linkages in A-431 Cells SEQ ID SEQ ID SEQ ID SEQ ID NO: 1 NO: 1 NO: 2 NO: 2 ATXN1 Compound Start Stop Start Stop (% SEQ Number Site Site Site Site Sequence (5′ to 3′) Control) ID NO 994308     6    25   2516   2535 CTGCGGTATACTCTGCTCTC  96  23 994316   305   324   1076  10735 GGAGGAGGAGATTGCTGTAC  13  24 994324   435   454 106177 106196 GTGCAGGCTGAAATCCACTC  32  25 994332   691   710 277909 277928 GTGTTCTTTCTTCCTTTCAC  37  26 994340   959   978 435678 435697 ATTTCATTTTTCGCCGTCCC  53  27 994348  1190  1209 435909 435928 CTTTGTGTAAACCTATTCCC  29  28 994356  1881  1900 436600 436619 TCAGCTTTCTTGGTGGCCTC 103  29 994364  2264  2283 436983 437002 GTGTGGTCTGAATGACCGTG  76  30 994372  2728  2747 437447 437466 GTCTTCCACCTTCTTTAGCT  65  31  994380*  2816  2835 437535 437554 GGCTGTCTTCAATCCTCTCT   4  32 994388  3139  3158 457392 457411 TCCGTTTTCCTGCTCGGCAT  32  33 994396  3398  3417 457651 457670 ACTTGCCTACATTAGACCGG  30  34 994404  3630  3649 457883 457902 ACCGCTCCTGCTGTGCCCTT  35  35 994412  4246  4265 458499 458518 CGCTCTCTCCCTCTCCCCCA  55  36 994420  4617  4636 458870 458889 TGTTTTTGTTTTTTCCCCAA   2  37 994428  4708  4727 458961 458980 ATTGAAACTTTCAATATCTT  50  38 994436  4858  4877 459111 459130 CCCTTTTCTCTCAGTTTCTC  37  39 994444  5428  5447 459681 459700 TTTTTTTTAAAGCACTTTAA  73  40 994452  5560  5579 459813 459832 GATTTTTTTTTTAATTTGTG  72  41 994460  5980  5999 460233 460252 TGTGTGTTTTTCTGAGTCCA   4  42 994468  6050  6069 460303 460322 GTGTTTTCCCATCTTAGTGT   7  43 994476  6324  6343 460577 460596 TGGGAGGCTCTCTCCCTCCT  86  44 994484  6937  6956 461190 461209 CGGTAAATATTGCAAAGTGG   4  45 994492  7083  7102 461336 461355 GTTTGTTGGTTTCTTATTAA   5  46 994500  7217  7236 461470 461489 GGCATCCATCTCTGTATCCC  34  47 994508  7868  7887 462121 462140 CATTGGAGATTTTTCTCTCT  17  48 994516  8196  8215 462449 462468 TCTCTATTTCAGAAATTCTG  34  49 994524  8379  8398 462632 462651 ATCTATGTAAAAGAAATCTC  58  50 994532  8542  8561 462795 462814 AATTTTTTAAAACATTACCT  57  51 994540  8764  8783 463017 463036 GGTATAGTTTAAGAGCCTTT  10  52 994548  9176  9195 463429 463448 GCCTCTTTATATTAAATAAA  76  53 994556  9296  9315 463549 463568 TCTGAATTTAAGAATTGTAA  52  54 994564  9707  9726 463960 463979 ACCTAATACTTGGTATTCTG  17  55 994572 10133 10152 464386 464405 GTGTCTGTTTTCCCTTGGCC   9  56 994580 10241 10260 464494 464513 GTATGCACTTAAAATTTTCT  11  57 994588 10381 10400 464634 464653 ATAGAATATGAATTCTTCCA  30  58 994596 10613 10632 464866 464885 ATTGGCACTGTTATTTTATT  48  59 994604 N/A N/A  15633  15652 GGCTCTTTAAATATTACTCC  63  60 994612 N/A N/A  31191  31210 GTTTGACTAGATGTGCTTCT   7  61 994620 N/A N/A  41645  41664 TCTTGAGCTTTTAATTTTAC  22  62 994628 N/A N/A  72785  72804 TGCTCCTTTTATCATTGTCA  16  63 994636 N/A N/A  94229  94248 CGGTGGTTTGTTGTACCCTT  62  64 994644 N/A N/A 111441 111460 TGTACTCTATAATTTTTTAA  82  65 994652 N/A N/A 134750 134769 TGAGCTGCTTTTCATATTCT  28  66 994660 N/A N/A 148412 148431 CAATAGACAAAAATTATCAT  78  67 149523 149542   994668 N/A N/A 148748 148767 TTTCCGAAGCTGCTATATGT  63  68 149859 149878 994676 N/A N/A 155724 155743 GTCTCTCTTTTTCTAAGTCA  46  69 994684 N/A N/A 169830 169849 AGACTAATATATATATATAT  52  70 170088 170107 994692 N/A N/A 180504 180523 GGGTCTCTTCATCTACCTTC  61  71 994700 N/A N/A 203037 203056 TGTTCCTTTCTTCTTTGTTC  21  72 994708 N/A N/A 219463 219482 GGGTGTGTATTCAATTCTCT  59  73 994716 N/A N/A 250181 250200 GTGACTTTAAAGCTTTCCTG  53  74 994724 N/A N/A 269848 269867 ACTGAGAGGCATCTCCAGTG  86  75 269877 269896 994732 N/A N/A 284341 284360 TGTCAACTAGTTCTTATCAC   7  76 994740 N/A N/A 306740 306759 GGTAAGGGCCACTAAATCTG   5  77 306826 306845 994748 N/A N/A 322467 322486 CTTACCACAGAGACATGCCC  56  78 323729 323748 994756 N/A N/A 332362 332381 GGAGTATTATAACAATTTGC   5  79 994764 N/A N/A 354092 354111 GTCTGGGCTGATGATGCTGG  16  80 994772 N/A N/A 369873 369892 GTCTGCCTTTAACATTTTTC  25  81 994780 N/A N/A 386759 386778 TGTTGTTTATAAGTTTACGG  12  82 994788 N/A N/A 406846 406865 TGCAGCTTATTTTATAGGTG   8  83 994796 N/A N/A 422947 422966 CGGTGTCTTAATATCCTCAG  32  84 994804 N/A N/A 437891 437910 GTTCCTCATCTTAATCACAG  24  85 994812 N/A N/A 439175 439194 GTGACTCATCTTGGCTACAG  32  86 994820 N/A N/A 440213 440232 ATTTTCCATGTGTCACCTGG  34  87 994828 N/A N/A 441396 441415 GTGCAGTGTCAGCAGTGCCT  44  88 994836 N/A N/A 443271 443290 GTTGTCTTACTGATCTGGAG  12  89 994844 N/A N/A 444292 444311 TGAGACCTCTCTCTACTTGC  43  90 994852 N/A N/A 445329 445348 TCAGTCCTTGGTGGAAGTGT  50  91 994860 N/A N/A 445809 445828 TCTGTTGTTTAAATATGTCT  49  92 994868 N/A N/A 446320 446339 TCTTTCATCTCTGGATGCCC  42  93 994876 N/A N/A 447587 447606 GTGTTCTATCTCCAGAGTCT  20  94 994884 N/A N/A 448144 448163 TGGTGAAGATAATGATGATC  28  95 994892 N/A N/A 449029 449048 TCCAGTTTTAATAAAAGTTC  61  96 994900 N/A N/A 451116 451135 ATTTTACTTAATTTTTACAA  77  97 994908 N/A N/A 452370 452389 ATGTGCATATATACATAGAC  23  98 994916 N/A N/A 453097 453116 CTTTTCTACTTCATCTTCTT  61  99 994924 N/A N/A 455432 455451 GTGTTCTCTGGTGAGCCCCA  59 100

TABLE 3  Reduction of ATXN1 RNA by 5-10-5 MOE gapmers with mixed PO/PS linkages in A-431 Cells SEQ ID SEQ ID SEQ ID SEQ ID NO: 1 NO: 1 NO: 2 NO: 2 ATXN1 Compound Start Stop Start Stop (% SEQ Number Site Site Site Site Sequence (5′ to 3′) Control) ID NO 994309    23 42   2533   2552 TGTAGTAGAAATGATGTCTG 75 101 994317   368 387 106110 106129 AAATAGACTCTTTCACTATG 41 102 994325   500 519 178110 178129 GTGGCAGTGGAGAATCTCAG 10 103 994333   761 780 277979 277998 TCAGCCTATACTTCACCATG 40 104 994341   965 984 435684 435703 GGTTGGATTTCATTTTTCGC 17 105 994349  1363 1382 436082 436101 TCCACTGTATTGGGAGGACC 73 106 994357  1882 1901 436601 436620 CTCAGCTTTCTTGGTGGCCT 93 107 994365  2455 2474 437174 437193 CGCTTCCATGTCAGTGCTGC 62 108 994373  2739 2758 437458 437477 TCTGTTTTTAAGTCTTCCAC 35 109  994381*  2848 2867 437567 437586 GGCGAACTGTATCACGGCCA 49 110 994389  3147 3166 457400 457419 TGGTTGATTCCGTTTTCCTG 63 111 994397  3467 3486 457720 457739 CCTACAGTACAGTAATCTGG 32 112 994405  3750 3769 458003 458022 CACGGGACTTTTCTCCTGAC 49 113 994413  4249 4268 458502 458521 GTTCGCTCTCTCCCTCTCCC 13 114 994421  4618 4637 458871 458890 TTGTTTTTGTTTTTTCCCCA  1 115 994429  4759 4778 459012 459031 CATTTATTGTCACATACTAG 19 116 994437  4922 4941 459175 459194 GGTTCTTTAAAAGTTCATCT  2 117 994445  5429 5448 459682 459701 CTTTTTTTTAAAGCACTTTA 37 118 994453  5571 5590 459824 459843 GGTTGATACCAGATTTTTTT 19 119 994461  5981 6000 460234 460253 GTGTGTGTTTTTCTGAGTCC  6 120 994469  6054 6073 460307 460326 ATGTGTGTTTTCCCATCTTA  8 121 994477  6421 6440 460674 460693 GTCTCCTTGGCTGGCTCTTT 21 122 994485  7018 7037 461271 461290 GTGTTCCATTGTAAACGCAA 36 123 994493  7087 7106 461340 461359 TCTTGTTTGTTGGTTTCTTA  3 124 994501  7243 7262 461496 461515 TCCACTTTAAAAGATCTGAG 18 125 994509  7892 7911 462145 462164 GCACGGTATTAGTGTCTTCA  6 126 994517  8204 8223 462457 462476 TCTTAAATTCTCTATTTCAG 34 127 994525  8487 8506 462740 462759 TCTTCAGCTTCTCAAATCAG 46 128 994533  8648 8667 462901 462920 TCTGCTTTTTTTTTTTTACA 45 129 994541  8867 8886 463120 463139 AAGTACTTTCAGCATAGGAA 13 130 994549  9189 9208 463442 463461 CGTATTTATTCTGGCCTCTT 14 131 994557  9428 9447 463681 463700 AATACAGTTGAACCATTTGT 28 132 994565  9725 9744 463978 463997 ACAGCTTGAGCTAGTGTCAC 32 133 994573 10135 10154 464388 464407 TGGTGTCTGTTTTCCCTTGG 16 134 994581 10311 10330 464564 464583 GGAATTACAGAGAGTATGCA 11 135 994589 10506 10525 464759 464778 GTTTTATTATAATAATGAAA 76 136 994597 198 217   9914   9933 GTAGTAGTTTTTGTGAGGTA 14 137 994605 N/A N/A  17726  17745 GTCACCTTTTCTATTTGCAC  6 138 994613 N/A N/A  33070  33089 ATTTTGACTTTTGATTGGTG 12 139 994621 N/A N/A  44962  44981 GGGACTCTGTCTTTATTTCC 75 140  44984  45003 994629 N/A N/A  77141  77160 ATGTTTCTATCTAAGTCCCA 40 141 994637 N/A N/A  98148  98167 GTGTGCATTTTTAATTTTGT 55 142 994645 N/A N/A 112180 112199 TGAGGACATCATGATGGTGC 20 143 994653 N/A N/A 139451 139470 GTTTTGTTTCAGTATTAGGT  3 144 994661 N/A N/A 148441 148460 TACATCCTGAAAATCACAGC 42 145 149552 149571 994669 N/A N/A 148797 148816 CTCTCACTTTTCTTCTCCTT 59 146 149908 149927 994677 N/A N/A 157700 157719 GTCTCCTTACATAGTGCTGC 42 147 994685 N/A N/A 169837 169856 ATATATTAGACTAATATATA 86 148 169922 169941 994693 N/A N/A 184184 184203 TCAGGTTTATATGTATACAA  7 149 994701 N/A N/A 203893 203912 GTTTGTTTAGATTTATCCTC  5 150 994709 N/A N/A 219913 219932 GTCATAGCTCTCCTCTGCAC 46 151 994717 N/A N/A 251504 251523 GTCAGCATACTTAGCTTTTC 16 152 994725 N/A N/A 269857 269876 CAGGGCTGGACTGAGAGGCA 58 153 269886 269905 994733 N/A N/A 288893 288912 TGAGACTATTATAGTTTCCA 12 154 994741 N/A N/A 308086 308105 TAAAATGCACCAATCAACGC 38 155 308110 308129 994749 N/A N/A 328172 328191 GTTACTTTATTTCTCTAGGG 10 156 994757 N/A N/A 333463 333482 ATTTGTCTTGTTGTATGTTG 15 157 994765 N/A N/A 355633 355652 GTTATTTTAAATAGTGGCCT 65 158 994773 N/A N/A 369913 369932 TCTTTGGCTTTTAGACCTGT 35 159 994781 N/A N/A 390011 390030 ATGTTATATCAATGTTCTGT  6 160 994789 N/A N/A 413612 413631 GTCTCAGCTCAAGAGTCTGT 75 161 994797 N/A N/A 430371 430390 TGGCCTGTATATCTATGGAC 75 162 994805 N/A N/A 438153 438172 TCAGCCATAGCTCACTACAG 26 163 994813 N/A N/A 439396 439415 GTCCCATTTGAATGTTTTCA 15 164 994821 N/A N/A 440225 440244 TCACTCATGTTTATTTTCCA 58 165 994829 N/A N/A 441413 441432 TCTGAATTTCTCTGTGGGTG 11 166 994837 N/A N/A 443454 443473 TGTACTCTTCAGAGAAGCTG 64 167 994845 N/A N/A 444302 444321 GTTAGGTGTGTGAGACCTCT 61 168 994853 N/A N/A 445380 445399 TCTGTGAGTGTTCTATTTAA 27 169 994861 N/A N/A 445876 445895 TGGTGCTATGTCTATATACA 25 170 994869 N/A N/A 446356 446375 TGGCCTTTATACTTTTGTAA 92 171 994877 N/A N/A 447624 447643 TGTATATTTGTCTGTTTTGC  9 172 994885 N/A N/A 448318 448337 CTTCCTTTTTTTATTTTGAG 17 173 994893 N/A N/A 449699 449718 TCTTTATTTTATAATTAGGT 63 174 994901 N/A N/A 451209 451228 TCTATGGTCCTCAGTCTCCT 57 175 994909 N/A N/A 452421 452440 GTGACACTATTTGGTTTCAA 59 176 994917 N/A N/A 453098 453117 GCTTTTCTACTTCATCTTCT 59 177 994925 N/A N/A 455497 455516 TGGGCTTTTGATAGTGTTAA 20 178

TABLE 4  Reduction of ATXN1 RNA by 5-10-5 MOE gapmers with mixed PO/PS linkages in A-431 Cells SEQ ID SEQ ID SEQ ID SEQ ID NO: 1 NO: 1 NO: 2 NO: 2 ATXN1 Compound Start Stop Start Stop (% SEQ Number Site Site Site Site Sequence (5′ to 3′) Control) ID NO 994310    99   118   2609   2628 GTTGCTCTGGCTGCTGCTCC  23 179 994318   413   432 106155 106174 TCTCTCTTGTTCCTGGTCTG   9 180 994326   515   534 178125 178144 GCTTGAGTAGAAAGGGTGGC  40 181 994334   879   898 435598 435617 GTCACATTTGATTTCTGTAG  12 182 994342   966   985 435685 435704 TGGTTGGATTTCATTTTTCG  24 183 994350  1550  1569 436269 436288 GCTGCTGCTGCTCAGCCTTG  62 184 994358  1889  1908 436608 436627 GGCTGCTCTCAGCTTTCTTG  89 185 994366  2554  2573 437273 437292 GTTGAAGTTCTCGCTCTTGG  23 186 994374  2740  2759 437459 437478 TTCTGTTTTTAAGTCTTCCA  30 187  994382*  2849  2868 437568 437587 CGGCGAACTGTATCACGGCC  30 188 994390  3154  3173 457407 457426 ACTCCCCTGGTTGATTCCGT  54 189 994398  3481  3500 457734 457753 CTGTGTTATTTTAGCCTACA   5 190 994406  3932  3951 458185 458204 GTTCCTGATGTTGATTTTGC  27 191 994414  4251  4270 458504 458523 GTGTTCGCTCTCTCCCTCTC  24 192 994422  4621  4640 458874 458893 TTTTTGTTTTTGTTTTTTCC  14 193 994430  4762  4781 459015 459034 GGTCATTTATTGTCACATAC   2 194 994438  4971  4990 459224 459243 ACTGCAGGAATATCACACAA  54 195 994446  5485  5504 459738 459757 GTTTAGTTGCAGCCATCCAA   8 196 994454  5572  5591 459825 459844 GGGTTGATACCAGATTTTTT  29 197 994462  5983  6002 460236 460255 TGGTGTGTGTTTTTCTGAGT   7 198 994470  6121  6140 460374 460393 ATTTTATAATTCCTATACCT  74 199 994478  6470  6489 460723 460742 CATTCACTATTCCGTGTGGT  41 200 994486  7024  7043 461277 461296 GTGATTGTGTTCCATTGTAA   5 201 994494  7088  7107 461341 461360 TTCTTGTTTGTTGGTTTCTT   5 202 994502  7384  7403 461637 461656 TCACAATTCCAAGTTAGAAA  16 203 994510  7930  7949 462183 462202 GTACCGAGAGCTCTGCTTCC  54 204 994518  8208  8227 462461 462480 GTGTTCTTAAATTCTCTATT   3 205 994526  8492  8511 462745 462764 TGTTTTCTTCAGCTTCTCAA  18 206 994534  8649  8668 462902 462921 CTCTGCTTTTTTTTTTTTAC  45 207 994542  8893  8912 463146 463165 GTTTAGACTAAGAAGGGAGC  22 208 994550  9191  9210 463444 463463 TCCGTATTTATTCTGGCCTC  32 209 994558  9462  9481 463715 463734 AGATACTACCTATTGGCCAA  63 210 994566  9758  9777 464011 464030 GCACCGAGCTTCTTGGTAAC  60 211 994574 10139 10158 464392 464411 GTTCTGGTGTCTGTTTTCCC   8 212 994582 10328 10347 464581 464600 GTACAATATTTTACACTGGA   5 213 994590 10548 10567 464801 464820 ATTTATTTAAAACAATTTTG  86 214 994598   201   220   9917   9936 CTTGTAGTAGTTTTTGTGAG  36 215 994606 N/A N/A  18215  18234 GGAGGGTGCTTAGTCCTTCC  69 216  18273  18292 994614 N/A N/A  34101  34120 GTTTGGCACACAGTAGGTGC  29 217 355035 355054 994622 N/A N/A  46490  46509 GTGACTGCTGCTGATACCTG  39 218 994630 N/A N/A  85516  85535 GTTTGATATGCTATGCTCAC  26 219 994638 N/A N/A  98883  98902 TGTTTGGTTGAAGTATGTGG  30 220 994646 N/A N/A 115266 115285 ATGTGGGTATTTAATGTTTC  17 221 994654 N/A N/A 140695 140714 GTCTTTCTAAATGGTTGTAC  31 222 994662 N/A N/A 148489 148508 TTCAGCATGATCTCAGTTCT  25 223 149600 149619 994670 N/A N/A 148889 148908 ATGACATAATTCTAATAACT  58 224 150000 150019 994678 N/A N/A 159922 159941 TCTCCTTATCTTGTCCTCTC  47 225 994686 N/A N/A 169926 169945 TATTATATATTAGACTAATA  81 226 170006 170025 994694 N/A N/A 185906 185925 GTTCTATTTTATAATAGTAG  70 227 994702 N/A N/A 210730 210749 TGTGTAATACTCCATTTTTC  18 228 994710 N/A N/A 223261 223280 GTTTGTGTTGTGTTTTACAG  19 229 994718 N/A N/A 251771 251790 GTTTTCATACACAGTTCTTC  23 230 994726 N/A N/A 270287 270306 ATTATATTACATTATACTTG 100 231 994734 N/A N/A 291014 291033 TCCTGGGTTTTTAGTTTTCC   4 232 994742 N/A N/A 310465 310484 TGAGGATTACATCAGTGTAA   4 233 994750 N/A N/A 328842 328861 TCTTGGGTAGATGAGGTTTG  11 234 994758 N/A N/A 337233 337252 TCTTGTTTTTTCCTTTCTTG  25 235 994766 N/A N/A 357070 357089 GTCTCCTTTGTTCCGTGTAC  21 236 994774 N/A N/A 372154 372173 GTCTTTTTATTTCTCTGCCC  11 237 994782 N/A N/A 396255 396274 TTGCAAGAAGGTATGCCTAG  61 238 396277 396296 994790 N/A N/A 413815 413834 TCCTGTTTACAACAAAGCTC  66 239 994798 N/A N/A 430661 430680 TCTTTCTTTGCTATAATTTC  84 240 994806 N/A N/A 438267 438286 GTCTGCTGATCTATCTGTTG  20 241 994814 N/A N/A 439492 439511 ATTAGTTTATCTTTTTTTTC  78 242 994822 N/A N/A 440914 440933 CTGTCAGTAGAGAGATTTAG  41 243 994830 N/A N/A 441421 441440 TGCACATTTCTGAATTTCTC  13 244 994838 N/A N/A 443819 443838 GTACCAGCTAATCCATTCAA  43 245 994846 N/A N/A 444486 444505 TGTTCTGTATAATAATGTAA  60 246 994854 N/A N/A 445456 445475 CGAGAGACCCATTTACTGCA  16 247 994862 N/A N/A 446068 446087 TGGGCTCATAATTATTTTTT  71 248 994870 N/A N/A 446878 446897 AAGTCATTTTATGATCTTGC  55 249 994878 N/A N/A 447631 447650 ATTTACTTGTATATTTGTCT  12 250 994886 N/A N/A 448328 448347 GTTTCCATAGCTTCCTTTTT  37 251 994894 N/A N/A 449737 449756 TCTCAAATAGGTACACTCAA  40 252 994902 N/A N/A 451578 451597 TTTTGTTTAAAGGGTTTTAC  85 253 994910 N/A N/A 452423 452442 GTGTGACACTATTTGGTTTC  49 254 994918 N/A N/A 453104 453123 ATTGTTGCTTTTCTACTTCA  73 255 994926 N/A N/A 455500 455519 AAGTGGGCTTTTGATAGTGT  20 256

TABLE 5  Reduction of ATXN1 RNA by 5-10-5 MOE gapmers with mixed PO/PS linkages in A-431 Cells SEQ ID SEQ ID SEQ ID SEQ ID NO: 1 NO: 1 NO: 2 NO: 2 ATXN1 Compound Start Stop Start Stop (% SEQ Number Site Site Site Site Sequence (5′ to 3′) Control) ID NO 994311   103   122   2613   2632 TGCTGTTGCTCTGGCTGCTG  62 257 994319   417   436 106159 106178 TCTTTCTCTCTTGTTCCTGG   5 258 994327   533   552 178143 178162 TCTTTTCACGAAGATTTTGC  22 259 994335   881   900 435600 435619 AAGTCACATTTGATTTCTGT  31 260 994343   969   988 435688 435707 TCTTGGTTGGATTTCATTTT  31 261 994351  1634  1653 436353 436372 TGAGGTGCTGCTGCTGCTGC  15 262 994359  1904  1923 436623 436642 TGGCCTGCTGCAGCCGGCTG  82 263 994367  2555  2574 437274 437293 GGTTGAAGTTCTCGCTCTTG  14 264 994375  2742  2761 437461 437480 TCTTCTGTTTTTAAGTCTTC  30 265 994383  2952  2971 457205 457224 TGGCTGGTTCTCTCCGGACA  71 266 994391  3245  3264 457498 457517 TGCTGGGTTCTATTTTGGTG  38 267 994399  3490  3509 457743 457762 ATGTAAATACTGTGTTATTT  32 268 994407  3933  3952 458186 458205 GGTTCCTGATGTTGATTTTG  33 269 994415  4254  4273 458507 458526 TGGGTGTTCGCTCTCTCCCT  37 270 994423  4636  4655 458889 458908 AAAGCAACTTAGTTTTTTTT  46 271 994431  4774  4793 459027 459046 GTAGTACTTGGTGGTCATTT  67 272 994439  5033  5052 459286 459305 TGCTACATTTATTTATGCTC  36 273 994447  5491  5510 459744 459763 TGTTCAGTTTAGTTGCAGCC   4 274 994455  5593  5612 459846 459865 AATACTAGACAGCCAAAATG  34 275 994463  5986  6005 460239 460258 AGGTGGTGTGTGTTTTTCTG   4 276 994471  6124  6143 460377 460396 ATTATTTTATAATTCCTATA  79 277 994479  6535  6554 460788 460807 TCCAGGCTACATGGCTCCAG  27 278 994487  7056  7075 461309 461328 ATTTTTTTCTTTTCGCCCTG  21 279 994495  7091  7110 461344 461363 AGGTTCTTGTTTGTTGGTTT   2 280 994503  7392  7411 461645 461664 ATAGAGGCTCACAATTCCAA  12 281 994511  8000  8019 462253 462272 TGTTGAGCTGCTTGTGGTTC  63 282 994519  8212  8231 462465 462484 TGATGTGTTCTTAAATTCTC  24 283 994527  8495  8514 462748 462767 TTTTGTTTTCTTCAGCTTCT  19 284 994535  8651  8670 462904 462923 TTCTCTGCTTTTTTTTTTTT  44 285 994543  8984  9003 463237 463256 CAAGATTATATTCTTTGGGT  11 286 994551  9194  9213 463447 463466 TGCTCCGTATTTATTCTGGC   3 287 994559  9472  9491 463725 463744 GTTATTGTATAGATACTACC  17 288 994567  9841  9860 464094 464113 GCACTAACTAAAGGATTTAC  14 289 994575 10146 10165 464399 464418 AACCCAAGTTCTGGTGTCTG  32 290 994583 10334 10353 464587 464606 GTGCAAGTACAATATTTTAC   5 291 994591 10601 10620 464854 464873 ATTTTATTAGTACGAGTATA  41 292 994599   204   223   9920   9939 GTGCTTGTAGTAGTTTTTGT  30 293 994607 N/A N/A  18221  18240 GTTAGTGGAGGGTGCTTAGT  24 294  18279  18298 994615 N/A N/A  39140  39159 TCCTGTTATTTTGGTACTGG  24 295 994623 N/A N/A  47154  47173 GTTTGCCTACTCCTGGTCTG  28 296 994631 N/A N/A  85766  85785 GTTGACTATCTTATTTTTTC  20 297 994639 N/A N/A  99612  99631 TCTTGCTTTTAATTTTTTTG  37 298 994647 N/A N/A 117178 117197 GTTCACCTACATGTTTCCCC  16 299 994655 N/A N/A 144856 144875 TCTTTTTTTTTTAATTACAG  79 300 994663 N/A N/A 148529 148548 TGGTGCACTCAGCTCTACCT  62 301 149640 149659 994671 N/A N/A 148965 148984 AAAAATCCTGATCAAAAAAA  76 302 150076 150095 994679 N/A N/A 160587 160606 GGCTCCATACTCCATTCTGT  40 303 994687 N/A N/A 170194 170213 TGTATAATATTCCATTCTGT  48 304 994695 N/A N/A 185938 185957 ATTTTATTACATTTTTCTTG  77 305 994703 N/A N/A 212031 212050 TCTATGTTAGTCATTTCTCT  98 306 994711 N/A N/A 223958 223977 TCTTGACATGATGTTTCCCT  60 307 994719 N/A N/A 256280 256299 ATTACCTTAAAACTACCTTG  54 308 994727 N/A N/A 271835 271854 TAAGCCATGCCTGGACTTCG  55 309 271877 271896 994735 N/A N/A 297005 297024 GTTTGCATTAAATGACTGTG   2 310 994743 N/A N/A 318485 318504 TGTTTGATATTTCTTTTTTT  10 311 994751 N/A N/A 328883 328902 TCTTGGGTAACTAGATGATG  15 312 994759 N/A N/A 341935 341954 GTTTTTTTTTTTATTTGCCT   4 313 994767 N/A N/A 357089 357108 GTCAGGTTATAATGACCCTG  49 314 994775 N/A N/A 376249 376268 TCTTCTGTATTTAATTCTTC  11 315 994783 N/A N/A 396693 396712 GTTATTGTGTTTATATTCAG  10 316 994791 N/A N/A 414662 414681 TGGTGACATCTTGTTTCTAC  15 317 994799 N/A N/A 433785 433804 TGAGCCACTGTGTGTAGCCA  52 318 994807 N/A N/A 438269 438288 TTGTCTGCTGATCTATCTGT  25 319 994815 N/A N/A 439696 439715 GTTTTTTATTTTTAAATTAG  62 320 994823 N/A N/A 441090 441109 CCTTGCACTTTTGTTTCTAC   7 321 994831 N/A N/A 442195 442214 TCAGTACATGTTCATCTTAA  10 322 994839 N/A N/A 443918 443937 CGGCATGTTCAATGTTGGCA  14 323 994847 N/A N/A 444822 444841 GTGAGCTATTATGGTGTCAC 101 324 994855 N/A N/A 445546 445565 GTCTGCTTTCCTGGAAGGCT  37 325 994863 N/A N/A 446159 446178 ATCCCCCTAAATCGACTCCT  63 326 994871 N/A N/A 446925 446944 GTTATTTTCTCTCCACTCTC  33 327 994879 N/A N/A 447641 447660 ATTCTTTTTTATTTACTTGT  43 328 994887 N/A N/A 448332 448351 TCTAGTTTCCATAGCTTCCT  17 329 994895 N/A N/A 450049 450068 TCTTTGTTTCTTTTTGCCTA   9 330 994903 N/A N/A 451583 451602 TCCATTTTTGTTTAAAGGGT  25 331 994911 N/A N/A 452493 452512 TGGTACAGATAATTGTGATG  29 332 994919 N/A N/A 453190 453209 TGGATTTTATACACATTCAG  49 333 994927 N/A N/A 456737 456756 CTTAGATTTTATGAGCTCAA  21 334

TABLE 6  Reduction of ATXN1 RNA by 5-10-5 MOE gapmers with mixed PO/PS linkages in A-431 Cells SEQ ID SEQ ID SEQ ID SEQ ID NO: 1 NO: 1 NO: 2 NO: 2 ATXN1 Compound Start Stop Start Stop (% SEQ Number Site Site Site Site Sequence (5′ to 3′) Control) ID NO 994312   105   124   2615   2634 GCTGCTGTTGCTCTGGCTGC  46 335 994320   418   437 106160 106179 CTCTTTCTCTCTTGTTCCTG   7 336 994328   562   581 178172 178191 ACCATAAGCTATCAGTTCCT   8 337 994336   916   935 435635 435654 GTCTGGATGGCTCTGATTTT  39 338 994344   974   993 435693 435712 TCCGCTCTTGGTTGGATTTC  63 339 994352  1637  1656 436356 436375 TGCTGAGGTGCTGCTGCTGC  31 340 994360  1927  1946 436646 436665 GTTCAGGACCTCCTTGGCCT  69 341 994368  2560  2579 437279 437298 CTCAGGGTTGAAGTTCTCGC  36 342  994376*  2758  2777 437477 437496 TGCACTCTGGATGAAATCTT  34 343 994384  3025  3044 457278 457297 CTTCAGGTTCTTGAGGGTAA  33 344 994392  3248  3267 457501 457520 GCTTGCTGGGTTCTATTTTG  93 345 994400  3546  3565 457799 457818 CCTGCTGTAACTCTAATGAC  40 346 994408  3987  4006 458240 458259 TGGTTAACTTTCCAAATCTG  16 347 994416  4283  4302 458536 458555 GTTTTCCTAACACTGCACAG  23 348 994424  4661  4680 458914 458933 ATGTAGTTACAGTGTTGAAA   5 349 994432  4777  4796 459030 459049 CAGGTAGTACTTGGTGGTCA  76 350 994440  5037  5056 459290 459309 ATTTTGCTACATTTATTTAT  53 351 994448  5496  5515 459749 459768 GTATTTGTTCAGTTTAGTTG   5 352 994456  5682  5701 459935 459954 GCTATTCTAAACCTATTCAA  75 353 994464  6029  6048 460282 460301 GGTTTAGTGGATCCAGTCAA   7 354 994472  6143  6162 460396 460415 AAGTGTTTAGAAAGAACCAA  41 355 994480  6702  6721 460955 460974 TGGCAGGTGGTCCCCTCCAC  68 356 994488  7064  7083 461317 461336 ATAGTATTATTTTTTTCTTT  68 357 994496  7095  7114 461348 461367 AGAGAGGTTCTTGTTTGTTG   6 358 994504  7447  7466 461700 461719 TGCTGCCACTTCCTGGTGGG  87 359 994512  8003  8022 462256 462275 GTCTGTTGAGCTGCTTGTGG  32 360 994520  8230  8249 462483 462502 CTCTGTATATTTATTACTTG   5 361 994528  8496  8515 462749 462768 ATTTTGTTTTCTTCAGCTTC  34 362 994536  8653  8672 462906 462925 CCTTCTCTGCTTTTTTTTTT  73 363 994544  8987  9006 463240 463259 GTTCAAGATTATATTCTTTG  21 364 994552  9235  9254 463488 463507 GTCCGGCTTGATTTTTGGAC  78 365 994560  9477  9496 463730 463749 TTGTTGTTATTGTATAGATA  21 366 994568  9935  9954 464188 464207 TTTAGAGTTGAGCAGTTCAG  20 367 994576 10167 10186 464420 464439 TGTCAGTCTGGTAGTGCCCT  18 368 994584 10362 10381 464615 464634 ATTTTTTAATATTTGTTTAA  75 369 994592 10604 10623 464857 464876 GTTATTTTATTAGTACGAGT  25 370 994600   205   224   9921   9940 GGTGCTTGTAGTAGTTTTTG  27 371 994608 N/A N/A  22131  22150 TCCTCCTTTTATATCTGTTT  72 372 994616 N/A N/A  39208  39227 GTTTGATTACTGTCATGACT  36 373 994624 N/A N/A  51696  51715 GTGAAAAGAAAGATGTACTT  82 374  51749  51768 994632 N/A N/A  85767  85786 CGTTGACTATCTTATTTTTT  26 375 994640 N/A N/A 103358 103377 TCTCAATTATAATTTGTTTT  71 376 994648 N/A N/A 118549 118568 GTTTCCTTAAAAGCAACTGT  24 377 994656 N/A N/A 148250 148269 AGAGTCAATGATTAAATTCA  29 378 149361 149380 994664 N/A N/A 148584 148603 CATGACTCTTTCTTAAGAAT  49 379 149695 149714 994672 N/A N/A 149011 149030 AAATTTTCTAGAAACATTAA  60 380 150122 150141 994680 N/A N/A 160737 160756 GTTACCATTCTCCTTTCCCC  50 381 994688 N/A N/A 170872 170891 TGCTAGCTACAGAGCACTGA 122 382 170939 170958 994696 N/A N/A 188547 188566 CGTTGGATATTTTATTCTTT   2 383 994704 N/A N/A 213149 213168 ATGTTTGTATTCCATATTTG  20 384 994712 N/A N/A 224696 224715 TCTTTTCATCTTCAGCTCTG  50 385 994720 N/A N/A 264945 264964 GTTTGTGCTTTTGGTGTCAC  14 386 994728 N/A N/A 275360 275379 GTTTGCTTTCTTCATCCTAC  45 387 994736 N/A N/A 299651 299670 AATCGCAGGGAGGATTGAAA  47 388 308026 308045 994744 N/A N/A 318885 318904 TGACCTTTATTTGGATCTTG  26 389 994752 N/A N/A 329899 329918 TGGCATTTATAATATTTGTG   2 390 994760 N/A N/A 347724 347743 ATTTTCTTAGAAGGATCTCT  10 391 994768 N/A N/A 359649 359668 GTTTGAACTGAGCATGTTTT  17 392 994776 N/A N/A 380393 380412 TGGTCATTAGATCATGCTAC  31 393 994784 N/A N/A 396974 396993 TGTAGCTTTTAGTGACTTTG  11 394 994792 N/A N/A 415670 415689 ATTTTGGCTTTCCATAGTGT  44 395 994800 N/A N/A 434146 434165 GTTACTGCTGCTGTGTGGGC  64 396 994808 N/A N/A 439027 439046 CTAGGATTAGCTAATTCCTA  78 397 994816 N/A N/A 439709 439728 TCTCTACTAAAATGTTTTTT  43 398 994824 N/A N/A 441169 441188 GGAGTATTTTAGCTGTGATG   6 399 994832 N/A N/A 442536 442555 GCTTCCTTTGGTGCACGCAG  34 400 994840 N/A N/A 444077 444096 GTTTGACATAGTTTCTCTGT  15 401 994848 N/A N/A 444899 444918 TGGTGTGTACTTGTGGTCCC  49 402 994856 N/A N/A 445653 445672 GTTTCAGTAAGTATGTCTTG  11 403 994864 N/A N/A 446193 446212 GTTATAAGAGATCTGCCTAC  70 404 994872 N/A N/A 446936 446955 ATCACACTTCAGTTATTTTC  31 405 994880 N/A N/A 447652 447671 TCTTCTTATGCATTCTTTTT  29 406 994888 N/A N/A 448391 448410 CCACCCACTGTCCTTTTCAG  58 407 994896 N/A N/A 450077 450096 ATTCTTCTTTAATCACTTCA  55 408 994904 N/A N/A 452108 452127 GTTTGCTTATTCTTGCCCAA  11 409 994912 N/A N/A 452497 452516 TCCATGGTACAGATAATTGT  53 410 994920 N/A N/A 453505 453524 GTTGGATTCTTTTTTTCTTT   5 411 994928 N/A N/A 456851 456870 TCTATAGCTGGTCTCTGTTA  54 412

TABLE 7  Reduction of ATXN1 RNA by 5-10-5 MOE gapmers with mixed PO/PS linkages in A-431 Cells SEQ ID SEQ ID SEQ ID SEQ ID NO: 1 NO: 1 NO: 2 NO: 2 ATXN1 Compound Start Stop Start Stop (% SEQ Number Site Site Site Site Sequence (5′ to 3′) Control) ID NO 994313   111   130   2621   2640 CTTGCGGCTGCTGTTGCTCT  28 413 994321   419   438 106161 106180 ACTCTTTCTCTCTTGTTCCT   7 414 994329   590   609 178200 178219 GTACCATGTGCTTTCATCAC  11 415 994337   924   943 435643 435662 GTTTCACTGTCTGGATGGCT  21 416 994345   977   996 435696 435715 TGCTCCGCTCTTGGTTGGAT  57 417 994353  1693  1712 436412 436431 GTACTGGTTCTGCTGGGCTG  32 418 994361  1949  1968 436668 436687 GCCGGCTCTTCTCCATCTCA  87 419 994369  2720  2739 437439 437458 CCTTCTTTAGCTCCCCGTTG  48 420  994377*  2768  2787 437487 437506 TGCTTATCTCTGCACTCTGG   6 421 994385  3034  3053 457287 457306 AGAGCCGTTCTTCAGGTTCT  90 422 994393  3279  3298 457532 457551 GCCGACCACCTCCTCTTCCT  89 423 994401  3568  3587 457821 457840 TGCACCAGTCTCCTGCGACA  41 424 994409  3999  4018 458252 458271 TGTTCTTTTAAATGGTTAAC  17 425 994417  4330  4349 458583 458602 GTTTGCATCTACCTCTTGGG  14 426 994425  4673  4692 458926 458945 TGCAGAGCTGAAATGTAGTT  38 427 994433  4780  4799 459033 459052 CGTCAGGTAGTACTTGGTGG  55 428 994441  5069  5088 459322 459341 AATGGCCTAGAGTTTAGGCA  81 429 994449  5499  5518 459752 459771 CAGGTATTTGTTCAGTTTAG   3 430 994457  5905  5924 460158 460177 TCCTCTTACCATCAAAGGCT  45 431 994465  6033  6052 460286 460305 TGTTGGTTTAGTGGATCCAG  13 432 994473  6194  6213 460447 460466 TGGCACAGAAAGTATTGCAC  34 433 994481  6716  6735 460969 460988 GTGGTGACCGTGGGTGGCAG  84 434 994489  7075  7094 461328 461347 GTTTCTTATTAATAGTATTA  38 435 994497  7125  7144 461378 461397 GTCATTTTATATATTTAGAA  74 436 994505  7454  7473 461707 461726 GGAGGGATGCTGCCACTTCC  67 437 994513  8005  8024 462258 462277 CAGTCTGTTGAGCTGCTTGT  55 438 994521  8232  8251 462485 462504 TTCTCTGTATATTTATTACT  42 439 994529  8503  8522 462756 462775 CTTCAAAATTTTGTTTTCTT  38 440 994537  8693  8712 462946 462965 TGACAAATTTCTATATACAA  66 441 994545  9036  9055 463289 463308 TGAGTCCTGTTTGATTGGTA   8 442 994553  9244  9263 463497 463516 GTTTCCACTGTCCGGCTTGA  29 443 994561  9486  9505 463739 463758 TCTTAGAGATTGTTGTTATT  12 444 994569  9942  9961 464195 464214 ATTTGGGTTTAGAGTTGAGC   6 445 994577 10193 10212 464446 464465 TCCCTAGTTCTCCTCTGTAC  74 446 994585 10365 10384 464618 464637 TCCATTTTTTAATATTTGTT  27 447 994593 10606 10625 464859 464878 CTGTTATTTTATTAGTACGA  42 448 994601   206   225   9922   9941 TGGTGCTTGTAGTAGTTTTT  33 449 994609 N/A N/A  22231  22250 TCTTCATTTTAATGTTGTTT  13 450 994617 N/A N/A  39411  39430 TCTGCTCTAAAACTTTCTAC  55 451 994625 N/A N/A  51702  51721 TTATTAGTGAAAAGAAAGAT  43 452  51755  51774 994633 N/A N/A  86196  86215 ATTCAGATATAATTGTTTAC  69 453 994641 N/A N/A 105012 105031 GTGTGAATAACTAATTCCTT  53 454 994649 N/A N/A 120191 120210 TGTTTGATAAATGTTATTCT  11 455 994657 N/A N/A 148273 148292 TATTATATTAAAAGTTAAAA  62 456 149384 149403 994665 N/A N/A 148615 148634 AGAGGCTTCTGGAAATCCCC  49 457 149726 149745 994673 N/A N/A 149065 149084 CCTGTCTTGATAAAATAAAA  96 458 150161 150180 994681 N/A N/A 162490 162509 TGCATCTATTTTCTATTCTG  96 459 994689 N/A N/A 176036 176055 GAAAATTCCTACTCATTTTT  99 460 176352 176371 994697 N/A N/A 189098 189117 GTTTCTGCTAATCTGTGACA  31 461 994705 N/A N/A 214840 214859 GTTTGCAGTTAACTTTTTTT  34 462 994713 N/A N/A 226996 227015 TGGTTATTTACTCATTCTAC  19 463 994721 N/A N/A 265218 265237 TCTTTTCATAAGCTTATTGG  71 464 994729 N/A N/A 279331 279350 GTCTGCTTTCAATGAAGCAC  69 465 994737 N/A N/A 299784 299803 ACTTTCCTGTCTTACAAGAG  19 466 299827 299846 994745 N/A N/A 320275 320294 GTGAGAACTGCTATTTTCAG   7 467 994753 N/A N/A 330357 330376 TCAGCTGTACAGCTCCTTAC  55 468 994761 N/A N/A 347823 347842 TGGTCATTATCTAGTTTCTG   5 469 994769 N/A N/A 365364 365383 GTGTGTCTAGTTTGTTTTTC  20 470 994777 N/A N/A 380610 380629 GTTATATATTTCCTATTTTC  34 471 994785 N/A N/A 398119 398138 TCTATATATTAATCATTTCC  68 472 994793 N/A N/A 417738 417757 GGGTTATATCATGTTGGCCA  67 473 994801 N/A N/A 437630 437649 CGGTGTGGTGTCCCATCCCT  71 474 994809 N/A N/A 439072 439091 CTTTGATATTTTAGTGTCTT  12 475 994817 N/A N/A 440059 440078 TCCTGATTTTCTTTTTTTTT  49 476 994825 N/A N/A 441229 441248 TGCTCTCTGTCTGAGTCTCC  68 477 994833 N/A N/A 442847 442866 GTGCCAGTTCCTGCATTTTC  43 478 994841 N/A N/A 444080 444099 GTGGTTTGACATAGTTTCTC   6 479 994849 N/A N/A 445236 445255 GTTTTTCTTACACATGGTAG  23 480 994857 N/A N/A 445654 445673 GGTTTCAGTAAGTATGTCTT   8 481 994865 N/A N/A 446197 446216 TGTGGTTATAAGAGATCTGC  28 482 994873 N/A N/A 446951 446970 TCATGATTTTATTGAATCAC  26 483 994881 N/A N/A 447992 448011 TCTTTATACCAGGGATCCCC 154 484 994889 N/A N/A 448705 448724 TCATACTTTCTTCCGCTCTT  38 485 994897 N/A N/A 450234 450253 GGGTTTCATTCACCATGTTG  47 486 994905 N/A N/A 452110 452129 CGGTTTGCTTATTCTTGCCC  43 487 994913 N/A N/A 452653 452672 ATTTTCTTTTTTCTGTGCCT   9 488 994921 N/A N/A 453506 453525 TGTTGGATTCTTTTTTTCTT  12 489 994929 N/A N/A 456930 456949 TGGGTTGTACCTCTACTTGC  69 490

TABLE 8  Reduction of ATXN1 RNA by 5-10-5 MOE gapmers with mixed PO/PS linkages in A-431 Cells SEQ ID SEQ ID SEQ ID SEQ ID NO: 1 NO: 1 NO: 2 NO: 2 ATXN1 Compound Start Stop Start Stop (% SEQ Number Site Site Site Site Sequence (5′ to 3′) Control) ID NO 994314   246   265  10657  10676 TGGTGACTTGATGCACGATG 10 491 994322   422   441 106164 106183 TCCACTCTTTCTCTCTTGTT 17 492 994330   687   706 277905 277924 TCTTTCTTCCTTTCACAGAG 35 493 994338   930   949 435649 435668 GTGACTGTTTCACTGTCTGG 79 494 994346   980   999 435699 435718 CGTTGCTCCGCTCTTGGTTG 47 495 994354  1870  1889 436589 436608 GGTGGCCTCCCGAGGGACAA 76 496 994362  2074  2093 436793 436812 ATCACGACTGCTGTAGTCTG 42 497 994370  2724  2743 437443 437462 TCCACCTTCTTTAGCTCCCC 71 498  994378*  2771  2790 437490 437509 CGTTGCTTATCTCTGCACTC 16 499 994386  3115  3134 457368 457387 GTGTCTGCTGCCCGCCAGGC 77 500 994394  3310  3329 457563 457582 TTCTGACTTCTCCAGTTTGC 75 501 994402  3618  3637 457871 457890 GTGCCCTTCCTCCCGCCCGC 77 502 994410  4028  4047 458281 458300 TTTATTGTAAAATATGTTGG 71 503 994418  4334  4353 458587 458606 GGCAGTTTGCATCTACCTCT 19 504 994426  4691  4710 458944 458963 CTTGCTCTTCAGCAATTCTG 52 505 994434  4824  4843 459077 459096 ATGCCTTGAACTGATTCTCA 13 506 994442  5218  5237 459471 459490 CTCACATATATAAATGTCTT 17 507 994450  5532  5551 459785 459804 AAAGTACTATTTTCAATGGG 23 508 994458  5915  5934 460168 460187 CAGCCCGTATTCCTCTTACC 19 509 994466  6034  6053 460287 460306 GTGTTGGTTTAGTGGATCCA 22 510 994474  6208  6227 460461 460480 TGGTCAGACTCTATTGGCAC 36 511 994482  6842  6861 461095 461114 TGTTTGCTACACAGAAGCGG 61 512 994490  7077  7096 461330 461349 TGGTTTCTTATTAATAGTAT 24 513 994498  7127  7146 461380 461399 CAGTCATTTTATATATTTAG 44 514 994506  7707  7726 461960 461979 GTGCAAAGAGTGGATTTTAT  6 515 994514  8063  8082 462316 462335 TGGCCCTGTTTTCACCTGGT 76 516 994522  8333  8352 462586 462605 GTTTGGAGTTTCCCTATGCC 13 517 994530  8509  8528 462762 462781 TGAGTGCTTCAAAATTTTGT 42 518 994538  8741  8760 462994 463013 GTAGTAATTCTTCCAGGCCA 25 519 994546  9047  9066 463300 463319 TGTCCCCATAATGAGTCCTG 32 520 994554  9249  9268 463502 463521 GTCCAGTTTCCACTGTCCGG 49 521 994562  9685  9704 463938 463957 GGACAGTATGTTATCTTGGT  8 522 994570  9953  9972 464206 464225 GGCTGACACTAATTTGGGTT 22 523 994578 10196 10215 464449 464468 CCTTCCCTAGTTCTCCTCTG 24 524 994586 10367 10386 464620 464639 CTTCCATTTTTTAATATTTG 38 525 994594 10608 10627 464861 464880 CACTGTTATTTTATTAGTAC 77 526 994602 N/A N/A   5488   5507 ATAAAAGTTGAGTAGCTAGA 68 527   6515   6534 994610 N/A N/A  28064  28083 TCCGCATTATTTTTCCCTGC  9 528 994618 N/A N/A  40728  40747 TCCTACTTTTAAGTTTCCAG 10 529 994626 N/A N/A  51710  51729 AAACTAATTTATTAGTGAAA 94 530  51763  51782 994634 N/A N/A  86436  86455 TGTATAGTAGAATTTTTTTT 77 531 994642 N/A N/A 106495 106514 GTGTGTTTAGTTGTTTGGGT  3 532 994650 N/A N/A 122443 122462 GTTGAGACTTAATTGCTCAG 67 533 994658 N/A N/A 149437 149456 GAATACTATGTATTTGCCAC 14 534 148326 148345 994666 N/A N/A 149806 149825 TTTTGACAAGTCAGTCTTTT 87 535 148695 148714 994674 N/A N/A 155493 155512 GTTTCCTTAAAATATGTTGG  9 536 994682 N/A N/A 163871 163890 TCCATTGTATATGTATCTGT 26 537 994690 N/A N/A 179789 179808 GTTATATTTAATCATGTTCC 13 538 994698 N/A N/A 189111 189130 GTCATATTTCTTAGTTTCTG  4 539 994706 N/A N/A 217284 217303 GTTATGTTTAAGGTATTTTC 21 540 994714 N/A N/A 234290 234309 CGTCGGATAAATTTATCCAC 80 541 994722 N/A N/A 265414 265433 GTTTTCTATAGTGATTGCAC 44 542 994730 N/A N/A 281189 281208 TCTTTTTTTCTTTTAACCCT  6 543 994738 N/A N/A 299793 299812 CAATCAGGAACTTTCCTGTC 65 544 308168 308187 994746 N/A N/A 322234 322253 AGGAACACAAGAGGGAATAC 53 545 323496 323515 994754 N/A N/A 331549 331568 TCTTTCCTAAAGCTTATTAG 52 546 994762 N/A N/A 352034 352053 GTTTTAACTCAGCTCTCTCT 53 547 994770 N/A N/A 366558 366577 CGGCTAGTATTTATATTTTT 48 548 994778 N/A N/A 382060 382079 GTCTACATTTATAGATTTAG 11 549 994786 N/A N/A 400669 400688 GTGTTACATAAATTAATTCC 14 550 994794 N/A N/A 418949 418968 GTTACTGTTCTTATCTTGTG 47 551 994802 N/A N/A 437850 437869 GGTGAGTTTCTGGATTGTCT  7 552 994810 N/A N/A 439073 439092 GCTTTGATATTTTAGTGTCT  6 553 994818 N/A N/A 440092 440111 TGAGCTGTATTATTATGCCA 68 554 994826 N/A N/A 441272 441291 TCCAGATATGAGTTCTCTCT 28 555 994834 N/A N/A 442868 442887 GTTCAGACTCAGATCTCTTC 27 556 994842 N/A N/A 444247 444266 ATAGTCTTTAATTTTTTTCT 88 557 994850 N/A N/A 445319 445338 GTGGAAGTGTTTCAGGGTTG 14 558 994858 N/A N/A 445807 445826 TGTTGTTTAAATATGTCTCC 23 559 994866 N/A N/A 446198 446217 GTGTGGTTATAAGAGATCTG 27 560 994874 N/A N/A 447042 447061 CAGTGCTTTCTCCAGGGTGT  3 561 994882 N/A N/A 447995 448014 TCCTCTTTATACCAGGGATC 47 562 994890 N/A N/A 448758 448777 ATCTCCATAAATGGTATCCC 37 563 994898 N/A N/A 450475 450494 GGAGAGAGAGAATATTTGAG 22 564 994906 N/A N/A 452112 452131 TGCGGTTTGCTTATTCTTGC 14 565 994914 N/A N/A 452981 453000 ACTTGAGTACATTCATATGG 57 566 994922 N/A N/A 453610 453629 ATCTAGATTGAAGTTTGTAC 94 567 994930 N/A N/A 456945 456964 TGAGGCTCTTCTCTTTGGGT 35 568

TABLE 9  Reduction of ATXN1 RNA by 5-10-5 MOE gapmers with mixed PO/PS linkages in A-431 Cells SEQ ID SEQ ID SEQ ID SEQ ID NO: 1 NO: 1 NO: 2 NO: 2 ATXN1 Compound Start Stop Start Stop (% SEQ Number Site Site Site Site Sequence (5′ to 3′) Control) ID NO 994315   295   314  10706  10725 ATTGCTGTACAAGGATGACA 16 569 994323   433   452 106175 106194 GCAGGCTGAAATCCACTCTT 20 570 994331   690   709 277908 277927 TGTTCTTTCTTCCTTTCACA 29 571 994339   932   951 435651 435670 CGGTGACTGTTTCACTGTCT 70 572 994347  1068  1087 435787 435806 CGGTGGTTGTCGCTGGGCAG 24 573 994355  1879  1898 436598 436617 AGCTTTCTTGGTGGCCTCCC 91 574 994363  2213  2232 436932 436951 GCTTCCCTAAATGCAGGCCA 64 575 994371  2727  2746 437446 437465 TCTTCCACCTTCTTTAGCTC 96 576  994379*  2812  2831 437531 437550 GTCTTCAATCCTCTCTACGG  3 577 994387  3127  3146 457380 457399 CTCGGCATACCTGTGTCTGC 58 578 994395  3313  3332 457566 457585 GTCTTCTGACTTCTCCAGTT 47 579 994403  3627  3646 457880 457899 GCTCCTGCTGTGCCCTTCCT 34 580 994411  4046  4065 458299 458318 ATACAATTAAAAGTTGCTTT 98 581 994419  4436  4455 458689 458708 ACCCGAGTTGTCCATAGTCA 12 582 994427  4701  4720 458954 458973 CTTTCAATATCTTGCTCTTC 25 583 994435  4856  4875 459109 459128 CTTTTCTCTCAGTTTCTCTG 23 584 994443  5219  5238 459472 459491 GCTCACATATATAAATGTCT 14 585 994451  5557  5576 459810 459829 TTTTTTTTTAATTTGTGAAA 95 586 994459  5979  5998 460232 460251 GTGTGTTTTTCTGAGTCCAC  3 587 994467  6040  6059 460293 460312 ATCTTAGTGTTGGTTTAGTG 14 588 994475  6231  6250 460484 460503 TGAGCTTTAACTATATAGCA 52 589 994483  6899  6918 461152 461171 TGGCTGATCCTTGTAAGCTG 64 590 994491  7080  7099 461333 461352 TGTTGGTTTCTTATTAATAG 12 591 994499  7151  7170 461404 461423 TCTTAAGTTAAACATTCTAA 49 592 994507  7839  7858 462092 462111 ATAGGTTTCCTTAGTAGTCA 17 593 994515  8068  8087 462321 462340 TCTGCTGGCCCTGTTTTCAC 23 594 994523  8356  8375 462609 462628 TCCGGAGTAGAGGTGTGCAA 68 595 994531  8510  8529 462763 462782 GTGAGTGCTTCAAAATTTTG 34 596 994539  8763  8782 463016 463035 GTATAGTTTAAGAGCCTTTT  8 597 994547  9121  9140 463374 463393 CATTGAAATCATGTTTTTAC 23 598 994555  9258  9277 463511 463530 CCCACAGCTGTCCAGTTTCC 62 599 994563  9700  9719 463953 463972 ACTTGGTATTCTGGAGGACA  6 600 994571 10096 10115 464349 464368 GGGTAATGATCTGATATTAA  5 601 994579 10239 10258 464492 464511 ATGCACTTAAAATTTTCTTT 10 602 994587 10368 10387 464621 464640 TCTTCCATTTTTTAATATTT 22 603 994595 10611 10630 464864 464883 TGGCACTGTTATTTTATTAG 41 604 994603 N/A N/A  15303  15322 TGCTCATTAAATAATTGCAG 57 605 994611 N/A N/A  28526  28545 GTGTCACTAGAAGATGCCCA 39 606 994619 N/A N/A  41522  41541 GTGCTCACTAATAATAGTCT 21 607 994627 N/A N/A  71054  71073 TCTCCTCTACTTAAGCTCAG 42 608 994635 N/A N/A  87298  87317 GTTTCCTATCCTGATTCCCA 43 609 994643 N/A N/A 106499 106518 GTTTGTGTGTTTAGTTGTTT 10 610 994651 N/A N/A 127663 127682 GTGACCACTCTCCTCCTCCC 55 611 994659 N/A N/A 148376 148395 AAGGTTTTCTCTTAAATATT 54 612 149487 149506 994667 N/A N/A 148746 148765 TCCGAAGCTGCTATATGTCA 51 613 149857 149876 994675 N/A N/A 155513 155532 GTGTGACACTATTATTCTTT 27 614 994683 N/A N/A 169801 169820 CGACCTTTAAAATTTTTTCA 63 615 994691 N/A N/A 180049 180068 ATTTGTTTACTTCTATATTG 65 616 994699 N/A N/A 198910 198929 GCTTCTTTAAATCTTAGCTC 72 617 994707 N/A N/A 218665 218684 GTTTGAGTCCAGTGACTTCT 44 618 994715 N/A N/A 244999 245018 TCTTGAGTTTATCTTTTCTT 36 619 994723 N/A N/A 269836 269855 CTCCAGTGCAGGGCTGGACT 86 620 269865 269884 269894 269913 994731 N/A N/A 284231 284250 GTTTGGGTTTTTCTGTACAA  2 621 994739 N/A N/A 305998 306017 TGGTAGGTATATAGATGTCC  3 622 994747 N/A N/A 322370 322389 ATCCCAATAAAAACATTCAG 61 623 323632 323651 994755 N/A N/A 331619 331638 TGTTCCATAGCTCATTTGCA  8 624 994763 N/A N/A 353740 353759 TGCTGTGTACTTAATTGACA 41 625 994771 N/A N/A 369407 369426 TCTTGTCTAGTTTTCTGCAG 54 626 994779 N/A N/A 384151 384170 GTCATTTTTGAACATATCCT 11 627 994787 N/A N/A 404260 404279 GTCTGTGTACCTCATTCTTT 13 628 994795 N/A N/A 420137 420156 GTGTGGGTGGCTGTGTCCTG 70 629 994803 N/A N/A 437851 437870 TGGTGAGTTTCTGGATTGTC  6 630 994811 N/A N/A 439088 439107 CTTTTATTTTCTGATGCTTT  7 631 994819 N/A N/A 440165 440184 GTAGTTCATTTTCTTTCTCC  6 632 994827 N/A N/A 441275 441294 AAGTCCAGATATGAGTTCTC 25 633 994835 N/A N/A 442870 442889 ATGTTCAGACTCAGATCTCT 26 634 994843 N/A N/A 444248 444267 AATAGTCTTTAATTTTTTTC 88 635 994851 N/A N/A 445325 445344 TCCTTGGTGGAAGTGTTTCA 57 636 994859 N/A N/A 445808 445827 CTGTTGTTTAAATATGTCTC 15 637 994867 N/A N/A 446255 446274 TCCTCCACTCTTTCCCTCCC 98 638 994875 N/A N/A 447189 447208 GTTTGCCTTCTGTATGGAAA 12 639 994883 N/A N/A 448112 448131 TGGAGCCTTGCTATGTTGGC 59 640 994891 N/A N/A 448954 448973 TGGTTAAGACCTAGTTTCTT 42 641 994899 N/A N/A 451089 451108 ATTTCTTGAGATGGATTCTC 24 642 994907 N/A N/A 452123 452142 TCTACCAGAGTTGCGGTTTG 53 643 994915 N/A N/A 453089 453108 CTTCATCTTCTTTGTTTCCT 36 644 994923 N/A N/A 455414 455433 CATTCTTTTGAGTTGTGACC 31 645 994931 N/A N/A 457057 457076 GTTTGATTTTATGCACACAC 63 646

Example 2: Effect of 5-10-5 MOE Gapmer Modified Oligonucleotides on Human ATXN1 RNA In Vitro, Single Dose

Modified oligonucleotides complementary to human ATXN1 nucleic acid were designed and tested for their single dose effects on ATXN1 mRNA in vitro. The modified oligonucleotides were tested in a series of experiments that had similar culture conditions.

The modified oligonucleotides in the tables below are 5-10-5 MOE gapmers with mixed internucleoside linkages. The gapmers are 20 nucleosides in length, wherein the central gap segment consists of ten 2′-β-D-deoxynucleosides and the 3′ and 5′ wings each consist of five 2′-MOE modified nucleosides. The motif for the gapmers is (from 5′ to 3′): eeeeeddddddddddeeeee; wherein “d” represents a 2′-β-D-deoxyribosyl sugar, and ‘e’ represents a 2′-MOE modified ribosyl sugar. The internucleoside linkage motif for the gapmers is (from 5′ to 3′): sooosssssssssssooss; wherein ‘o’ represents a phosphodiester internucleoside linkage and ‘s’ represents a phosphorothioate internucleoside linkage. Each cytosine residue is a 5-methyl cytosine.

“Start site” indicates the 5′-most nucleoside to which the modified oligonucleotide is complementary in the human gene sequence. “Stop site” indicates the 3′-most nucleoside to which the modified oligonucleotide is complementary in the human gene sequence. Each modified oligonucleotide listed in the Tables below is 100% complementary to SEQ ID NO: 1, SEQ ID NO: 2, or SEQ ID NO: 3 (GENBANK Accession No. NM_001128164.1). ‘N/A’ indicates that the modified oligonucleotide is not 100% complementary to that particular gene sequence.

Cultured A-431 cells were treated with modified oligonucleotide at a concentration of 4,000 nM by free uptake at a density of 10,000 cells per well for a treatment period of 48 hours. At the end of their treatment period, total RNA was isolated from the cells and ATXN1 RNA levels were measured by quantitative real-time RTPCR. ATXN1 RNA levels were measured by Human ATXN1 primer probe set RTS37575 (forward sequence GTATAGGCTGAGGCTACCTGT, designated herein as SEQ ID NO: 14; reverse sequence GATCCAGGCTCTTCATGAGG, designated herein as SEQ ID NO: 15; probe sequence ACAGCAGCTCTGGATGAACATTCACT, designated herein as SEQ ID NO: 16). ATXN1 RNA levels were normalized to total RNA content, as measured by RIBOGREEN®. Results are presented in the tables below as percent ATXN1 RNA levels relative to untreated control cells (% Control). The Compound No. marked with an asterisk (*) indicates that the modified oligonucleotide is complementary to the amplicon region of the primer probe set. Additional assays may be used to measure the potency and efficacy of the modified oligonucleotides complementary to the amplicon region.

TABLE 10  Reduction of ATXN1 RNA by 5-10-5 MOE gapmers with mixed PO/PS linkages in A-431 Cells SEQ ID SEQ ID SEQ ID SEQ ID NO: 1 NO: 1 NO: 2 NO: 2 ATXN1 Compound Start Stop Start Stop (% SEQ Number Site Site Site Site Sequence (5′ to 3′) Control) ID NO  994605 N/A N/A  17726  17745 GTCACCTTTTCTATTTGCAC   4 138 1040079   468   487 N/A N/A AGACCAAAAACCATTTGTGT   9 647 1040111  2755  2774 437474 437493 ACTCTGGATGAAATCTTCTG  71 648 1040143  3244  3263 457497 457516 GCTGGGTTCTATTTTGGTGA  46 649 1040175  4029  4048 458282 458301 TTTTATTGTAAAATATGTTG  90 650 1040207  4510  4529 458763 458782 GATAGTAATATATGCTCATC   9 651 1040239  4767  4786 459020 459039 TTGGTGGTCATTTATTGTCA   8 652 1040271  5224  5243 459477 459496 ATCTTGCTCACATATATAAA  33 653 1040303  5589  5608 459842 459861 CTAGACAGCCAAAATGTGGG  29 654 1040335  6017  6036 460270 460289 CCAGTCAATTCAATACTCGA  14 655 1040367  6475  6494 460728 460747 CTCCACATTCACTATTCCGT  13 656 1040399  7152  7171 461405 461424 TTCTTAAGTTAAACATTCTA  75 657 1040431  7622  7641 461875 461894 GGAGTAATCCACAAGATGCA  48 658 1040463  8111  8130 462364 462383 TCCTTTCACATCACCACCGA  42 659 1040495  8375  8394 462628 462647 ATGTAAAAGAAATCTCAGCT  42 660 1040527  8696  8715 462949 462968 ACATGACAAATTTCTATATA  79 661 1040559  9109  9128 463362 463381 GTTTTTACTCCCCCCATTTA 106 662 1040591  9441  9460 463694 463713 TGCACTTAATTTTAATACAG  24 663 1040623  9885  9904 464138 464157 GGGCAGTATTCACAGAACTG  27 664 1040655 10254 10273 464507 464526 TCTTAACTATTATGTATGCA  18 665 1040687 10527 10546 464780 464799 TCAAATTTTGAATCAAACAT  88 666 1040719 N/A N/A  17960  17979 TGAGTGCACATTTAATCTTT  11 667 1040751 N/A N/A  31937  31956 TTGTCATATTTTTATAGCAT  76 668 1040783 N/A N/A  51100  51119 TGTTCATTCCCTTAGTAACT  21 669 1040815 N/A N/A  77282  77301 GGCAAGATCTTTTAAAGTCC  18 670 1040847 N/A N/A  94809  94828 AGACTGTTTCTTTACCACAT  14 671 1040879 N/A N/A 118132 118151 TCCACCAGTATTTATGGAGT 119 672 1040911 N/A N/A 151437 151456 CTTTAGTATTTTTATCATTA  40 673 1040943 N/A N/A 179378 179397 AACAGTACAATTTACTTGAC  56 674 1040975 N/A N/A 195960 195979 CCTTTAAAAACCAACACAGT  84 675 1041007 N/A N/A 216607 216626 TCTTGTCATTTTTAACATCC  28 676 1041039 N/A N/A 237165 237184 ACTCAATTTTAAAGACTCGG  38 677 1041071 N/A N/A 258705 258724 ATGTGTTGAATTTAACCAGC  22 678 1041103 N/A N/A 276428 276447 CTCATTAATTAAATCATTCG 105 679 1041135 N/A N/A 295010 295029 CACCTAAAAATACAGGAAGT  76 680 1041167 N/A N/A 324809 324828 CCAAGAATTTAAAAAGGACA  42 681 1041199 N/A N/A 345760 345779 TGTCTCAAACTATTCCCATT  26 682 1041231 N/A N/A 371655 371674 TTAACAATCTTTTAGACCTG  24 683 1041263 N/A N/A 393703 393722 GACATATTTCAAAAATGCAA  68 684 1041295 N/A N/A 426181 426200 AACTTGTTTCAAAGTGAGAG  88 685 1041327 N/A N/A 437896 437915 TCAGGGTTCCTCATCTTAAT  24 686 1041359 N/A N/A 438301 438320 AGAGAGTATAAAAATTATCT  72 687 1041391 N/A N/A 438910 438929 GCAGCCTCCTATATTGGTCC  40 688 1041423 N/A N/A 439178 439197 CCAGTGACTCATCTTGGCTA  48 689 1041455 N/A N/A 439863 439882 TGGTCCTTTCCTCACTTGGG  27 690 1041487 N/A N/A 440220 440239 CATGTTTATTTTCCATGTGT   8 691 1041519 N/A N/A 440788 440807 ACACACCTAGATCTTCCTCC  49 692 1041551 N/A N/A 441387 441406 CAGCAGTGCCTAACCAGTTG  43 693 1041583 N/A N/A 441652 441671 TGCCAGAGACCCAAATCCGC  64 694 1041615 N/A N/A 442276 442295 TCATCCCCAAACTAAACACC 100 695 1041647 N/A N/A 442821 442840 GCTAACCTACTTCCTACCCA  59 696 1041679 N/A N/A 443177 443196 CATGACATCATTTAGCCTTA  12 697 1041711 N/A N/A 443557 443576 GGCCCTAATAACACAGAGCC 113 698 1041743 N/A N/A 444006 444025 GCGGCACAAATCCAGGGCTG  71 699 1041775 N/A N/A 444407 444426 GTAGTATAAACTATGGACTT  26 700 1041807 N/A N/A 445306 445325 AGGGTTGTTCAGTAAACCCA 134 701 1041839 N/A N/A 445658 445677 GCTAGGTTTCAGTAAGTATG   9 702 1041871 N/A N/A 445920 445939 ACACGCATATTTATGCTGTT  64 703 1041903 N/A N/A 446128 446147 ACCTCCAACTCCCATTTTGG  54 704 1041935 N/A N/A 446724 446743 GTAAATATATCCTGTTTCAA  59 705 1041967 N/A N/A 446975 446994 TCACCTTGTCAGATGCTGAG  45 706 1041999 N/A N/A 447909 447928 GGTGAGCAACCATTCCAGAC  74 707 1042031 N/A N/A 448558 448577 CTCGGTCACCACATGCAAGC 102 708 1042063 N/A N/A 448821 448840 GACCTAAAACACACCAGACC  78 709 1042095 N/A N/A 449388 449407 ATAGCTTCAAAATATTGTTA  31 710 1042127 N/A N/A 449700 449719 ATCTTTATTTTATAATTAGG  87 711 1042159 N/A N/A 449981 450000 GATGCCACGACCAGATATCA  73 712 1042191 N/A N/A 450575 450594 ACCAAACTCCAAATCTCCAA  38 713 1042223 N/A N/A 451243 451262 TCAACCTTCTTGAACCCTCA  62 714 1042255 N/A N/A 451690 451709 TCATTATTTCCGCATCTCAA  13 715 1042287 N/A N/A 451970 451989 CCGGACACCTACCCATGGAG  82 716 1042319 N/A N/A 452312 452331 CACTGTATTCTAAGTAGGAG  81 717 1042351 N/A N/A 452637 452656 GCCTCCTGACCTCTACCCTT  56 718 1042383 N/A N/A 453119 453138 AGTAGATTTCCACAGATTGT  26 719 1042415 N/A N/A 453901 453920 AGCCTCTAGAACAAAATACA  97 720 1042447 N/A N/A 455088 455107 AGCTTGAGAATTTTGATAGG  22 721 1042479 N/A N/A 455365 455384 GAACCACAAGCCAACAGGCC  89 722 1042511 N/A N/A 456665 456684 ACTGTGAGTTCCAAGAAGCA  49 723

TABLE 11  Reduction of ATXN1 RNA by 5-10-5 MOE gapmers with mixed PO/PS linkages in A-431 Cells SEQ ID SEQ ID SEQ ID SEQ ID NO: 1 NO: 1 NO: 2 NO: 2 ATXN1 Compound Start Stop Start Stop (% SEQ Number Site Site Site Site Sequence (5′ to 3′) Control) ID NO  994605 N/A N/A  17726  17745 GTCACCTTTTCTATTTGCAC   3 138  1040080*   824   843 435543 435562 TGGGTACAATCCGCCAACAG  32 724 1040112  2813  2832 437532 437551 TGTCTTCAATCCTCTCTACG  65 725 1040144  3334  3353 457587 457606 AGGAAGAGTCAAAGGTGGTT  41 726 1040176  4034  4053 458287 458306 GTTGCTTTTATTGTAAAATA  29 727 1040208  4512  4531 458765 458784 AAGATAGTAATATATGCTCA  11 728 1040240  4802  4821 459055 459074 CATCAAAGTGAAAAGTGCCT  48 729 1040272  5278  5297 459531 459550 CCATTCTGAAAATAACATTA  15 730 1040304  5614  5633 459867 459886 GGTGAACCCTAAATGTAAAT  40 731 1040336  6018  6037 460271 460290 TCCAGTCAATTCAATACTCG  26 732 1040368  6478  6497 460731 460750 ACACTCCACATTCACTATTC  55 733 1040400  7162  7181 461415 461434 ACTGAAATAATTCTTAAGTT 108 734 1040432  7653  7672 461906 461925 AGCATTATATTGCAATCTAT  31 735 1040464  8113  8132 462366 462385 TCTCCTTTCACATCACCACC  27 736 1040496  8385  8404 462638 462657 GAGGTCATCTATGTAAAAGA  15 737 1040528  8697  8716 462950 462969 GACATGACAAATTTCTATAT  12 738 1040560  9114  9133 463367 463386 ATCATGTTTTTACTCCCCCC  48 739 1040592  9454  9473 463707 463726 CCTATTGGCCAAATGCACTT  46 740 1040624  9970  9989 464223 464242 TCTTGAAACCTCCTTTCGGC  74 741 1040656 10255 10274 464508 464527 CTCTTAACTATTATGTATGC  25 742 1040688 10529 10548 464782 464801 GTTCAAATTTTGAATCAAAC  39 743 1040720 N/A N/A  18197  18216 CCCAAATTTCAAAGGTCCTT   6 744 1040752 N/A N/A  32181  32200 GTGGTCAAAGAATCTGTTTC  10 745 1040784 N/A N/A  51766  51785 TAGAAACTAATTTATTAGTG 119 746 1040816 N/A N/A  77793  77812 ACACAGATTATTTATAGTCA  13 747 1040848 N/A N/A  96129  96148 CACTTTCTAGATTATTCTTA  84 748 1040880 N/A N/A 118292 118311 ACTCTCTACCTTTAAGATTT  28 749 1040912 N/A N/A 153619 153638 CATCTATTTATTTACCTTCT  30 750 1040944 N/A N/A 179493 179512 GAACTTAAAATTCCCTAGGA 111 751 1040976 N/A N/A 195968 195987 TCTTTTAACCTTTAAAAACC  53 752 1041008 N/A N/A 216637 216656 ACCTGCTTTCAAAAGTCAAA  72 753 1041040 N/A N/A 238066 238085 CAAGTAATACAAATCCACAG  65 754 1041072 N/A N/A 259575 259594 CAGGACTTATTTTATATATG  32 755 1041104 N/A N/A 276769 276788 CTTCCCAAATACATCATCGA 101 756 1041136 N/A N/A 295238 295257 CATTTAAAAACTGTACATGG  20 757 1041168 N/A N/A 324921 324940 ATCTAAATTTAAACTGCACA  31 758 1041200 N/A N/A 347770 347789 TGGTCAATAATTTATATGGC   2 759 1041232 N/A N/A 372753 372772 AACTATTATATTTATAGATT 108 760 1041264 N/A N/A 395038 395057 AGCTGTAAAATATATCCCTG   8 761 1041296 N/A N/A 427897 427916 AACCTTACTTAAATATCTCA  62 762 1041328 N/A N/A 437897 437916 ATCAGGGTTCCTCATCTTAA  11 763 1041360 N/A N/A 438322 438341 GTGCCCTTTCCTCTTGGGAT  58 764 1041392 N/A N/A 438914 438933 CCCAGCAGCCTCCTATATTG  91 765 1041424 N/A N/A 439182 439201 ACTTCCAGTGACTCATCTTG  34 766 1041456 N/A N/A 439866 439885 ATTTGGTCCTTTCCTCACTT  28 767 1041488 N/A N/A 440222 440241 CTCATGTTTATTTTCCATGT  31 768 1041520 N/A N/A 440796 440815 AGGGAAAAACACACCTAGAT  39 769 1041552 N/A N/A 441389 441408 GTCAGCAGTGCCTAACCAGT  41 770 1041584 N/A N/A 441726 441745 ACAGAAAAACAAAACTCATT 105 771 1041616 N/A N/A 442285 442304 CCTTAAAAATCATCCCCAAA  99 772 1041648 N/A N/A 442823 442842 CAGCTAACCTACTTCCTACC  90 773 1041680 N/A N/A 443212 443231 TCAGAAATACAGATTGATAT  44 774 1041712 N/A N/A 443559 443578 ACGGCCCTAATAACACAGAG  94 775 1041744 N/A N/A 444009 444028 ACTGCGGCACAAATCCAGGG  32 776 1041776 N/A N/A 444408 444427 TGTAGTATAAACTATGGACT  23 777 1041808 N/A N/A 445316 445335 GAAGTGTTTCAGGGTTGTTC   8 778 1041840 N/A N/A 445659 445678 AGCTAGGTTTCAGTAAGTAT   7 779 1041872 N/A N/A 445921 445940 TACACGCATATTTATGCTGT  98 780 1041904 N/A N/A 446135 446154 AACTGTCACCTCCAACTCCC  57 781 1041936 N/A N/A 446727 446746 CCAGTAAATATATCCTGTTT  26 782 1041968 N/A N/A 446985 447004 CATAGCCACCTCACCTTGTC  72 783 1042000 N/A N/A 447963 447982 GCAACAGACCAGTAGCAGTC  79 784 1042032 N/A N/A 448600 448619 TACCTCCACCACCTTTGTCC  63 785 1042064 N/A N/A 448823 448842 GTGACCTAAAACACACCAGA  37 786 1042096 N/A N/A 449389 449408 GATAGCTTCAAAATATTGTT  20 787 1042128 N/A N/A 449708 449727 GCAAATCTATCTTTATTTTA  79 788 1042160 N/A N/A 449991 450010 CCTGCGAAAAGATGCCACGA 117 789 1042192 N/A N/A 450674 450693 AAGTTCAGTTACAGAGGTGC  19 790 1042224 N/A N/A 451247 451266 GTTCTCAACCTTCTTGAACC 110 791 1042256 N/A N/A 451693 451712 CTTTCATTATTTCCGCATCT  14 792 1042288 N/A N/A 451971 451990 GCCGGACACCTACCCATGGA 132 793 1042320 N/A N/A 452314 452333 CCCACTGTATTCTAAGTAGG  82 794 1042352 N/A N/A 452646 452665 TTTTTCTGTGCCTCCTGACC  59 795 1042384 N/A N/A 453143 453162 AAGTACCAAAAAAACTTTAA  77 796 1042416 N/A N/A 454243 454262 AGCCTCTAGAACAGGCTGGG 131 797 1042448 N/A N/A 455090 455109 ACAGCTTGAGAATTTTGATA  21 798 1042480 N/A N/A 455370 455389 ACAGTGAACCACAAGCCAAC 107 799 1042512 N/A N/A 456692 456711 ACAGGACTAAACATGGATCA  39 800

TABLE 12  Reduction of ATXN1 RNA by 5-10-5 MOE gapmers with mixed PO/PS linkages in A-431 Cells SEQ ID SEQ ID SEQ ID SEQ ID NO: 1 NO: 1 NO: 2 NO: 2 ATXN1 Compound Start Stop Start Stop (% SEQ Number Site Site Site Site Sequence (5′ to 3′) Control) ID NO  994605 N/A N/A  17726  17745 GTCACCTTTTCTATTTGCAC   1 138  1040081*   856   875 435575 435594 ATCCAGGCTCTTCATGAGGA   5 801 1040113  2819  2838 437538 437557 TATGGCTGTCTTCAATCCTC  53 802 1040145  3369  3388 457622 457641 CAAATCTTAACCTCCTGAGG  48 803 1040177  4047  4066 458300 458319 TATACAATTAAAAGTTGCTT 110 804 1040209  4531  4550 458784 458803 CAGTATTTTTAAATGCTTAA  35 805 1040241  4815  4834 459068 459087 ACTGATTCTCAGACATCAAA  40 806 1040273  5279  5298 459532 459551 GCCATTCTGAAAATAACATT   9 807 1040305  5616  5635 459869 459888 CTGGTGAACCCTAAATGTAA  43 808 1040337  6019  6038 460272 460291 ATCCAGTCAATTCAATACTC  10 809 1040369  6480  6499 460733 460752 CCACACTCCACATTCACTAT  35 810 1040401  7190  7209 461443 461462 CCCCTCTGCCCCAGTGTGGC  96 811 1040433  7656  7675 461909 461928 TGCAGCATTATATTGCAATC  74 812 1040465  8114  8133 462367 462386 CTCTCCTTTCACATCACCAC  30 813 1040497  8417  8436 462670 462689 TCCTATCATCAGTAAGGTAA  92 814 1040529  8711  8730 462964 462983 AATCTGATCATTTAGACATG  42 815 1040561  9115  9134 463368 463387 AATCATGTTTTTACTCCCCC  76 816 1040593  9464  9483 463717 463736 ATAGATACTACCTATTGGCC  39 817 1040625  9971  9990 464224 464243 ATCTTGAAACCTCCTTTCGG  55 818 1040657 10257 10276 464510 464529 AGCTCTTAACTATTATGTAT  16 819 1040689 10559 10578 464812 464831 GTATACAGACAATTTATTTA  83 820 1040721 N/A N/A  18359  18378 ACATGGTATTTTTATCAGTC   3 821 1040753 N/A N/A  33291  33310 CCTAACAAAATTTCCCTTCA  73 822 1040785 N/A N/A  53624  53643 GTGAATTTTCCTTAAATTTC  23 823 1040817 N/A N/A  77899  77918 TGCAAATTCTAAAAATTACT 101 824 1040849 N/A N/A  96635  96654 TTCTTGTTTCAAAGTGAGGA 121 825 1040881 N/A N/A 118343 118362 GACCTCATCCATTATAATAT  52 826 1040913 N/A N/A 153709 153728 CCAACCAACCAAAAACTCAC 101 827 1040945 N/A N/A 179793 179812 CATAGTTATATTTAATCATG  64 828 1040977 N/A N/A 196970 196989 ATGCCTCACCTTTAAATAGT  82 829 1041009 N/A N/A 217125 217144 GACAAGTTTATTTATTTTTC  25 830 1041041 N/A N/A 239500 239519 AACTGATTTCAAAGTCAGAC 131 831 1041073 N/A N/A 260025 260044 ACTGAAACTTTTTAACATAC  37 832 1041105 N/A N/A 278198 278217 CAGCAAATACAAACAGGACC   3 833 1041137 N/A N/A 295336 295355 ACACAGTTACAAATCAATGC   1 834 1041169 N/A N/A 324924 324943 TGGATCTAAATTTAAACTGC   6 835 1041201 N/A N/A 348183 348202 ATGCTCAAACCTCATTCATT  23 836 1041233 N/A N/A 373954 373973 TACTCCTTATTTTAAATATA 114 837 1041265 N/A N/A 395428 395447 AAGGTTCTATTTTATATGCC  24 838 1041297 N/A N/A 428019 428038 AGTGTTAGAGAATACTTTTC  33 839 1041329 N/A N/A 437898 437917 AATCAGGGTTCCTCATCTTA  26 840 1041361 N/A N/A 438362 438381 TGCCCCCCACTTTACGGTGT  98 841 1041393 N/A N/A 438931 438950 CAGTCCAGAGCCCACTCCCC  96 842 1041425 N/A N/A 439188 439207 AACCATACTTCCAGTGACTC  10 843 1041457 N/A N/A 439897 439916 CCAGTCATTCACGAGTGGTT  60 844 1041489 N/A N/A 440232 440251 TGACTCTTCACTCATGTTTA  67 845 1041521 N/A N/A 440798 440817 GTAGGGAAAAACACACCTAG  87 846 1041553 N/A N/A 441417 441436 CATTTCTGAATTTCTCTGTG  15 847 1041585 N/A N/A 441728 441747 CCACAGAAAAACAAAACTCA 100 848 1041617 N/A N/A 442286 442305 CCCTTAAAAATCATCCCCAA 103 849 1041649 N/A N/A 442824 442843 GCAGCTAACCTACTTCCTAC  24 850 1041681 N/A N/A 443215 443234 TACTCAGAAATACAGATTGA  62 851 1041713 N/A N/A 443563 443582 ACAGACGGCCCTAATAACAC 106 852 1041745 N/A N/A 444022 444041 TGTATTACCAACAACTGCGG  37 853 1041777 N/A N/A 444419 444438 ACAGAGTGAACTGTAGTATA   3 854 1041809 N/A N/A 445337 445356 AGCCTGACTCAGTCCTTGGT 122 855 1041841 N/A N/A 445672 445691 GAATTCTCTCATAAGCTAGG  51 856 1041873 N/A N/A 445928 445947 ATGCACATACACGCATATTT  57 857 1041905 N/A N/A 446161 446180 CCATCCCCCTAAATCGACTC  84 858 1041937 N/A N/A 446729 446748 ATCCAGTAAATATATCCTGT  15 859 1041969 N/A N/A 447005 447024 GGCAGCTTTCTCAGCGGAGC  65 860 1042001 N/A N/A 447978 447997 ATCCCCAACCCCCAGGCAAC 110 861 1042033 N/A N/A 448602 448621 ACTACCTCCACCACCTTTGT  57 862 1042065 N/A N/A 448825 448844 AAGTGACCTAAAACACACCA  88 863 1042097 N/A N/A 449390 449409 TGATAGCTTCAAAATATTGT  30 864 1042129 N/A N/A 449710 449729 TAGCAAATCTATCTTTATTT  70 865 1042161 N/A N/A 450005 450024 AGGAGCTGTGTCACCCTGCG  71 866 1042193 N/A N/A 450685 450704 CAGCCAAACCTAAGTTCAGT  32 867 1042225 N/A N/A 451248 451267 AGTTCTCAACCTTCTTGAAC  78 868 1042257 N/A N/A 451698 451717 AAAGCCTTTCATTATTTCCG   9 869 1042289 N/A N/A 452004 452023 CCGGATAACTCCCTGTCTCC  80 870 1042321 N/A N/A 452315 452334 ACCCACTGTATTCTAAGTAG  23 871 1042353 N/A N/A 452658 452677 AACCCATTTTCTTTTTTCTG 119 872 1042385 N/A N/A 453188 453207 GATTTTATACACATTCAGAC  58 873 1042417 N/A N/A 454279 454298 CATCTTGTAAACTAAACAGG  58 874 1042449 N/A N/A 455116 455135 GCTTACAATAATTAAGAAGA  60 875 1042481 N/A N/A 455372 455391 AGACAGTGAACCACAAGCCA  95 876 1042513 N/A N/A 456694 456713 GGACAGGACTAAACATGGAT  23 877

TABLE 13  Reduction of ATXN1 RNA by 5-10-5 MOE gapmers with mixed PO/PS linkages in A-431 Cells SEQ ID SEQ ID SEQ ID SEQ ID NO: 1 NO: 1 NO: 2 NO: 2 ATXN1 Compound Start Stop Start Stop (% SEQ Number Site Site Site Site Sequence (5′ to 3′) Control) ID NO  994605 N/A N/A  17726  17745 GTCACCTTTTCTATTTGCAC   2 138 1040082   896   915 435615 435634 AGTCTGATAAACGGAAAGTC  58 878 1040114  2839  2858 437558 437577 TATCACGGCCACGCCCGGGC 149 879 1040146  3372  3391 457625 457644 ATGCAAATCTTAACCTCCTG  12 880 1040178  4048  4067 458301 458320 CTATACAATTAAAAGTTGCT 111 881 1040210  4532  4551 458785 458804 ACAGTATTTTTAAATGCTTA  52 882 1040242  4816  4835 459069 459088 AACTGATTCTCAGACATCAA  39 883 1040274  5306  5325 459559 459578 GATTTGATTTTGAATAGAAA  64 884 1040306  5617  5636 459870 459889 CCTGGTGAACCCTAAATGTA  66 885 1040338  6025  6044 460278 460297 TAGTGGATCCAGTCAATTCA  22 886 1040370  6483  6502 460736 460755 TCTCCACACTCCACATTCAC  87 887 1040402  7241  7260 461494 461513 CACTTTAAAAGATCTGAGGT  51 888 1040434  7676  7695 461929 461948 GCTACTGTTCATCTTGAACA  76 889 1040466  8123  8142 462376 462395 AGTGTAATTCTCTCCTTTCA  17 890 1040498  8426  8445 462679 462698 AAGAAAAGATCCTATCATCA  76 891 1040530  8716  8735 462969 462988 ATACAAATCTGATCATTTAG  60 892 1040562  9116  9135 463369 463388 AAATCATGTTTTTACTCCCC  81 893 1040594  9466  9485 463719 463738 GTATAGATACTACCTATTGG  27 894 1040626  9991 10010 464244 464263 CCACAAATACTGACAGGACT  18 895 1040658 10258 10277 464511 464530 AAGCTCTTAACTATTATGTA  28 896 1040690 10561 10580 464814 464833 TGGTATACAGACAATTTATT  58 897 1040722 N/A N/A  18895  18914 AACTTTAAAACCAAAGAGCC  89 898 1040754 N/A N/A  33435  33454 TGTACAATAATATATTTCTT  63 899 1040786 N/A N/A  53693  53712 GCAGAAATTCATTAAAAAGG  44 900 1040818 N/A N/A  78103  78122 TACTGGTATATTTATTTGTT  25 901 1040850 N/A N/A  96906  96925 CTTGAGTTTCATTATCTCCT  62 902 1040882 N/A N/A 122955 122974 CATACATTCCCTTAAGCCAA  45 903 1040914 N/A N/A 154008 154027 AGTATTATTTAAAACTACAT 107 904 1040946 N/A N/A 180271 180290 CCATGGTTTCAAAGCTCTGT  68 905 1040978 N/A N/A 198120 198139 AGCTATAAAATATAAACTTC 116 906 1041010 N/A N/A 218069 218088 AGCTTTTGAATTTATTATGA  63 907 1041042 N/A N/A 240054 240073 CAGAGACTATTTTAAAGACG  67 908 1041074 N/A N/A 262925 262944 CTCTTATTTTAAACTGGTGC  17 909 1041106 N/A N/A 279276 279295 TTACTGATTATTTAACCCTG   1 910 1041138 N/A N/A 296194 296213 AGTTCATTTTAAACTGTATT   1 911 1041170 N/A N/A 326365 326384 TGTATTATTTTCTAACAGAA  17 912 1041202 N/A N/A 349100 349119 AAGTATACAATTTAAGGATC  18 913 1041234 N/A N/A 374001 374020 ATTAGATTTCCTTACTGCAA  16 914 1041266 N/A N/A 395704 395723 CCTCTCAAAACCACTTTTAT 123 915 1041298 N/A N/A 428253 428272 CCCTCAATTCAAAGACAAAT 128 916 1041330 N/A N/A 437904 437923 TTTCCTAATCAGGGTTCCTC  24 917 1041362 N/A N/A 438363 438382 GTGCCCCCCACTTTACGGTG  35 918 1041394 N/A N/A 438955 438974 CCTGACTTTCATATGCAAAC  23 919 1041426 N/A N/A 439190 439209 TTAACCATACTTCCAGTGAC  49 920 1041458 N/A N/A 439905 439924 CCCCATATCCAGTCATTCAC  91 921 1041490 N/A N/A 440236 440255 GCAATGACTCTTCACTCATG  49 922 1041522 N/A N/A 440800 440819 GAGTAGGGAAAAACACACCT  49 923 1041554 N/A N/A 441434 441453 AAGCTCAACAATTTGCACAT  37 924 1041586 N/A N/A 441742 441761 ACGAACACAAAAACCCACAG  65 925 1041618 N/A N/A 442287 442306 CCCCTTAAAAATCATCCCCA  84 926 1041650 N/A N/A 442825 442844 AGCAGCTAACCTACTTCCTA  34 927 1041682 N/A N/A 443218 443237 TCATACTCAGAAATACAGAT  19 928 1041714 N/A N/A 443616 443635 TTAAGCAGCCACCGAGTCAG  94 929 1041746 N/A N/A 444023 444042 GTGTATTACCAACAACTGCG   8 930 1041778 N/A N/A 444443 444462 TTCATCAAAAACAGCATGTA  85 931 1041810 N/A N/A 445344 445363 CACGCAAAGCCTGACTCAGT  50 932 1041842 N/A N/A 445673 445692 TGAATTCTCTCATAAGCTAG  96 933 1041874 N/A N/A 445931 445950 ACTATGCACATACACGCATA 108 934 1041906 N/A N/A 446163 446182 ATCCATCCCCCTAAATCGAC  54 935 1041938 N/A N/A 446730 446749 CATCCAGTAAATATATCCTG  17 936 1041970 N/A N/A 447020 447039 CTTTACCGCCTAACAGGCAG 123 937 1042002 N/A N/A 447979 447998 GATCCCCAACCCCCAGGCAA  94 938 1042034 N/A N/A 448606 448625 TTTTACTACCTCCACCACCT  61 939 1042066 N/A N/A 448836 448855 ACTCAAACTTAAAGTGACCT  66 940 1042098 N/A N/A 449409 449428 TGGGTATTCTCTATGATGCT  26 941 1042130 N/A N/A 449713 449732 TCATAGCAAATCTATCTTTA  74 942 1042162 N/A N/A 450017 450036 GCTTCCTACCAAAGGAGCTG 128 943 1042194 N/A N/A 450686 450705 GCAGCCAAACCTAAGTTCAG  78 944 1042226 N/A N/A 451252 451271 AAGAAGTTCTCAACCTTCTT  91 945 1042258 N/A N/A 451699 451718 GAAAGCCTTTCATTATTTCC  29 946 1042290 N/A N/A 452046 452065 TAGTTCCAAACATGTCAGCC  29 947 1042322 N/A N/A 452353 452372 GACAAATATACTTACAAGTG  17 948 1042354 N/A N/A 452664 452683 CCCCCAAACCCATTTTCTTT 121 949 1042386 N/A N/A 453191 453210 TTGGATTTTATACACATTCA  45 950 1042418 N/A N/A 454294 454313 GCTATAAATCAAAGACATCT  61 951 1042450 N/A N/A 455117 455136 TGCTTACAATAATTAAGAAG  75 952 1042482 N/A N/A 455402 455421 TTGTGACCCCAAAGCACTGT 100 953 1042514 N/A N/A 456708 456727 GCTATTATCATACAGGACAG  20 954

TABLE 14  Reduction of ATXN1 RNA by 5-10-5 MOE gapmers with mixed PO/PS linkages in A-431 Cells SEQ ID SEQ ID SEQ ID SEQ ID NO: 1 NO: 1 NO: 2 NO: 2 ATXN1 Compound Start Stop Start Stop (% SEQ Number Site Site Site Site Sequence (5′ to 3′) Control) ID NO  994605 N/A N/A  17726  17745 GTCACCTTTTCTATTTGCAC   3 138 1040083   902   921 435621 435640 GATTTTAGTCTGATAAACGG  32 955 1040115  2852  2871 437571 437590 CGACGGCGAACTGTATCACG 120 956 1040147  3386  3405 457639 457658 TAGACCGGCCTTCAATGCAA  41 957 1040179  4050  4069 458303 458322 ATCTATACAATTAAAAGTTG 116 958 1040211  4534  4553 458787 458806 GAACAGTATTTTTAAATGCT  13 959 1040243  4817  4836 459070 459089 GAACTGATTCTCAGACATCA  15 960 1040275  5323  5342 459576 459595 ACCAAACATTAAATCTCGAT  36 961 1040307  5636  5655 459889 459908 GTTTATAAAAATCATTAGTC  76 962 1040339  6064  6083 460317 460336 GCTCCAAACCATGTGTGTTT  23 963 1040371  6493  6512 460746 460765 GCCTCCTTCCTCTCCACACT  54 964 1040403  7244  7263 461497 461516 TTCCACTTTAAAAGATCTGA  34 965 1040435  7696  7715 461949 461968 GGATTTTATGATTACTAGGA   9 966 1040467  8151  8170 462404 462423 GGCCTCCACGCCACTTAAAA 144 967 1040499  8432  8451 462685 462704 TGCTACAAGAAAAGATCCTA  63 968 1040531  8722  8741 462975 462994 ATAACCATACAAATCTGATC  61 969 1040563  9124  9143 463377 463396 TTACATTGAAATCATGTTTT  48 970 1040595  9467  9486 463720 463739 TGTATAGATACTACCTATTG  53 971 1040627  9996 10015 464249 464268 GGTCACCACAAATACTGACA  29 972 1040659 10269 10288 464522 464541 TGTCACAATAAAAGCTCTTA  47 973 1040691 10563 10582 464816 464835 ACTGGTATACAGACAATTTA  80 974 1040723 N/A N/A  19256  19275 CCCAGCAAAGCCATCCAGTG  80 975 1040755 N/A N/A  33606  33625 TTGATTACAATTTAAATTCA  90 976 1040787 N/A N/A  54456  54475 AAGGGAATATTTTACTTTAT  13 977 1040819 N/A N/A  78391  78410 CTATTATTATTTTACTGGCA   7 978 1040851 N/A N/A  97882  97901 TTTTATAGCCACTAACCAAC  96 979 1040883 N/A N/A 125349 125368 AACATATTTCATTATAATTC 100 980 1040915 N/A N/A 154957 154976 ACCCAGCATTTTTAACATTA  63 981 1040947 N/A N/A 180483 180502 CTTTCATTTATTTAGTGAAA 116 982 1040979 N/A N/A 200076 200095 TTCCTTACTTTTTAGGATAC 119 983 1041011 N/A N/A 218138 218157 GATTTATTTTAAAGTACTCT  83 984 1041043 N/A N/A 241942 241961 GATTCCAAAACCAGACTTGT 143 985 1041075 N/A N/A 263175 263194 CCATATATAGATTACAAAGC  39 986 1041107 N/A N/A 281181 281200 TCTTTTAACCCTAAGACTGT  67 987 1041139 N/A N/A 296440 296459 TGACAGTATTTTTAAAGACT   2 988 1041171 N/A N/A 326617 326636 ACTGGCAAACCCAAAAGCTA 103 989 1041203 N/A N/A 349644 349663 ACTGTTAAAACCCATCCAAC  63 990 1041235 N/A N/A 374559 374578 ATGCAGTTCTAAAAGAAAGC  66 991 1041267 N/A N/A 397171 397190 AGGCCCAAACCTCTAATCAA 123 992 1041299 N/A N/A 429792 429811 AAGATTCAAATATATCTTAA 130 993 1041331 N/A N/A 437924 437943 GGACCTGAAGTCCAGCAGCG  60 994 1041363 N/A N/A 438401 438420 ACTCCCTCCACCTCCTGACC 101 995 1041395 N/A N/A 438956 438975 GCCTGACTTTCATATGCAAA  45 996 1041427 N/A N/A 439210 439229 GCCTGTGGAAATTAAGAGCG 101 997 1041459 N/A N/A 439912 439931 TGCAAGCCCCCATATCCAGT  45 998 1041491 N/A N/A 440261 440280 TTAAGGATTCTAAGTACCAT  20 999 1041523 N/A N/A 440821 440840 TCATTAATTTTGCAAAGTTT  19 1000 1041555 N/A N/A 441445 441464 TTTTGCTTATTAAGCTCAAC  49 1001 1041587 N/A N/A 441743 441762 AACGAACACAAAAACCCACA 105 1002 1041619 N/A N/A 442289 442308 AGCCCCTTAAAAATCATCCC 116 1003 1041651 N/A N/A 442826 442845 AAGCAGCTAACCTACTTCCT  53 1004 1041683 N/A N/A 443220 443239 GTTCATACTCAGAAATACAG  33 1005 1041715 N/A N/A 443625 443644 CACTGAATATTAAGCAGCCA  76 1006 1041747 N/A N/A 444024 444043 TGTGTATTACCAACAACTGC  69 1007 1041779 N/A N/A 444458 444477 ACATGACATCATAAATTCAT  38 1008 1041811 N/A N/A 445353 445372 AATCATGTTCACGCAAAGCC  41 1009 1041843 N/A N/A 445675 445694 AATGAATTCTCTCATAAGCT  69 1010 1041875 N/A N/A 445943 445962 CTATATCTAAACACTATGCA  79 1011 1041907 N/A N/A 446164 446183 CATCCATCCCCCTAAATCGA 100 1012 1041939 N/A N/A 446731 446750 TCATCCAGTAAATATATCCT  21 1013 1041971 N/A N/A 447021 447040 GCTTTACCGCCTAACAGGCA  92 1014 1042003 N/A N/A 447994 448013 CCTCTTTATACCAGGGATCC  83 1015 1042035 N/A N/A 448607 448626 TTTTTACTACCTCCACCACC  93 1016 1042067 N/A N/A 448839 448858 GCAACTCAAACTTAAAGTGA  46 1017 1042099 N/A N/A 449410 449429 ATGGGTATTCTCTATGATGC  22 1018 1042131 N/A N/A 449715 449734 ATTCATAGCAAATCTATCTT 102 1019 1042163 N/A N/A 450018 450037 TGCTTCCTACCAAAGGAGCT 129 1020 1042195 N/A N/A 450687 450706 AGCAGCCAAACCTAAGTTCA  61 1021 1042227 N/A N/A 451307 451326 ACCCTCTATTAAAAATACTA 113 1022 1042259 N/A N/A 451702 451721 TTTGAAAGCCTTTCATTATT  85 1023 1042291 N/A N/A 452049 452068 CCTTAGTTCCAAACATGTCA  42 1024 1042323 N/A N/A 452358 452377 ACATAGACAAATATACTTAC  31 1025 1042355 N/A N/A 452665 452684 GCCCCCAAACCCATTTTCTT 113 1026 1042387 N/A N/A 453354 453373 ATGCACCACCACCACCACGC  79 1027 1042419 N/A N/A 454295 454314 TGCTATAAATCAAAGACATC  93 1028 1042451 N/A N/A 455129 455148 TTACAAAGACTATGCTTACA  68 1029 1042483 N/A N/A 455404 455423 AGTTGTGACCCCAAAGCACT  94 1030 1042515 N/A N/A 456709 456728 TGCTATTATCATACAGGACA  21 1031

TABLE 15  Reduction of ATXN1 RNA by 5-10-5 MOE gapmers with mixed PO/PS linkages in A-431 Cells SEQ ID SEQ ID SEQ ID SEQ ID NO: 1 NO: 1 NO: 2 NO: 2 ATXN1 Compound Start Stop Start Stop (% SEQ Number Site Site Site Site Sequence (5′ to 3′) Control) ID NO  994605 N/A N/A  17726  17745 GTCACCTTTTCTATTTGCAC   2  138 1040084   909   928 435628 435647 TGGCTCTGATTTTAGTCTGA  34 1032 1040116  2895  2914 457148 457167 TACTCTACCAAAACTTCAAC  75 1033 1040148  3387  3406 457640 457659 TTAGACCGGCCTTCAATGCA  39 1034 1040180  4134  4153 458387 458406 GCAGAAATGAAATCCCGCAT  31 1035 1040212  4586  4605 458839 458858 TGAGATACAGTACTTGTTGA  12 1036 1040244  4866  4885 459119 459138 TTCTCCATCCCTTTTCTCTC  25 1037 1040276  5325  5344 459578 459597 GTACCAAACATTAAATCTCG  43 1038 1040308  5638  5657 459891 459910 CGGTTTATAAAAATCATTAG  80 1039 1040340  6065  6084 460318 460337 TGCTCCAAACCATGTGTGTT  42 1040 1040372  6500  6519 460753 460772 TGAATCTGCCTCCTTCCTCT  29 1041 1040404  7245  7264 461498 461517 TTTCCACTTTAAAAGATCTG  51 1042 1040436  7699  7718 461952 461971 AGTGGATTTTATGATTACTA   9 1043 1040468  8176  8195 462429 462448 GGTTAAAAACAAATGTGGAA 132 1044 1040500  8481  8500 462734 462753 GCTTCTCAAATCAGGTGTAC  11 1045 1040532  8726  8745 462979 462998 GGCCATAACCATACAAATCT  74 1046 1040564  9177  9196 463430 463449 GGCCTCTTTATATTAAATAA 135 1047 1040596  9510  9529 463763 463782 TCAGATAAGAAAAGTTATGG  54 1048 1040628  9997 10016 464250 464269 AGGTCACCACAAATACTGAC  36 1049 1040660 10275 10294 464528 464547 TTCTCCTGTCACAATAAAAG  93 1050 1040692 10565 10584 464818 464837 GTACTGGTATACAGACAATT  95 1051 1040724 N/A N/A  20058  20077 GTCCTCAAAACCTATGGAGC 127 1052 1040756 N/A N/A  34396  34415 TGGCTTAACCAGGGAGATGT  13 1053 1040788 N/A N/A  56211  56230 ACTGATAATTTTTAGACATA  41 1054 1040820 N/A N/A  79273  79292 ACCTCAATCATTTACTCTCT  22 1055 1040852 N/A N/A  99200  99219 ACTCCTAAAATTTATTGAGG 124 1056 1040884 N/A N/A 127408 127427 CCCTGAATAGTCTATGCCAT  37 1057 1040916 N/A N/A 155491 155510 TTCCTTAAAATATGTTGGCA  43 1058 1040948 N/A N/A 181346 181365 GGAAACAACCAAAAACTGCT  32 1059 1040980 N/A N/A 202475 202494 TGACACAATATTTACTGTGT  99 1060 1041012 N/A N/A 218314 218333 TCTCAGTTTCAAAATAGGAC  32 1061 1041044 N/A N/A 241960 241979 CCTCAAAAAGAATCTGCAGA 102 1062 1041076 N/A N/A 263468 263487 TCGGTTACTATTTACCTTTC  60 1063 1041108 N/A N/A 281316 281335 GGACCCTAAATTTAAACAGC   2 1064 1041140 N/A N/A 296918 296937 TGGAAATTTCAAAAAGCTAA  32 1065 1041172 N/A N/A 327619 327638 AACAACAAATAATTACCTAT 114 1066 1041204 N/A N/A 350026 350045 AAGGAAAATCAAACATTGCT   7 1067 1041236 N/A N/A 375439 375458 AGGTCTAGTATTTATCTTCT   1 1068 1041268 N/A N/A 398360 398379 GAAACATTATTTTACTTTTC  65 1069 1041300 N/A N/A 430468 430487 TCCTAAAAATACATCTTAAA 102 1070 1041332 N/A N/A 437957 437976 CTGGTAAGAAAAAGTGCCGA 120 1071 1041364 N/A N/A 438416 438435 GCCACATTTCCCCTCACTCC  23 1072 1041396 N/A N/A 438957 438976 AGCCTGACTTTCATATGCAA  56 1073 1041428 N/A N/A 439250 439269 GTAATCGATCTAAGAACCTG  21 1074 1041460 N/A N/A 439916 439935 TTTGTGCAAGCCCCCATATC 103 1075 1041492 N/A N/A 440277 440296 TGTTCACAAAAATGTGTTAA  71 1076 1041524 N/A N/A 440828 440847 CATTTAATCATTAATTTTGC  63 1077 1041556 N/A N/A 441446 441465 ATTTTGCTTATTAAGCTCAA  38 1078 1041588 N/A N/A 441811 441830 CCAATGATCCCATCACTGCA 103 1079 1041620 N/A N/A 442290 442309 CAGCCCCTTAAAAATCATCC 105 1080 1041652 N/A N/A 442846 442865 TGCCAGTTCCTGCATTTTCC   8 1081 1041684 N/A N/A 443222 443241 CAGTTCATACTCAGAAATAC  50 1082 1041716 N/A N/A 443626 443645 GCACTGAATATTAAGCAGCC  93 1083 1041748 N/A N/A 444025 444044 GTGTGTATTACCAACAACTG  16 1084 1041780 N/A N/A 444459 444478 TACATGACATCATAAATTCA  56 1085 1041812 N/A N/A 445359 445378 ACACTGAATCATGTTCACGC   7 1086 1041844 N/A N/A 445679 445698 GAGCAATGAATTCTCTCATA  27 1087 1041876 N/A N/A 445945 445964 TACTATATCTAAACACTATG 115 1088 1041908 N/A N/A 446169 446188 TCCTCCATCCATCCCCCTAA  75 1089 1041940 N/A N/A 446740 446759 CCCATTTTTTCATCCAGTAA  12 1090 1041972 N/A N/A 447022 447041 GGCTTTACCGCCTAACAGGC 107 1091 1042004 N/A N/A 447996 448015 CTCCTCTTTATACCAGGGAT  85 1092 1042036 N/A N/A 448608 448627 TTTTTTACTACCTCCACCAC 105 1093 1042068 N/A N/A 448842 448861 TGGGCAACTCAAACTTAAAG  57 1094 1042100 N/A N/A 449424 449443 AATTTAAAACCCATATGGGT 115 1095 1042132 N/A N/A 449743 449762 CACACATCTCAAATAGGTAC  54 1096 1042164 N/A N/A 450034 450053 GCCTAAATTCTGCCTTTGCT  35 1097 1042196 N/A N/A 450690 450709 GTGAGCAGCCAAACCTAAGT  45 1098 1042228 N/A N/A 451308 451327 AACCCTCTATTAAAAATACT 111 1099 1042260 N/A N/A 451730 451749 CTAAAGACTTCATAATGTTA  58 1100 1042292 N/A N/A 452051 452070 AGCCTTAGTTCCAAACATGT 107 1101 1042324 N/A N/A 452368 452387 GTGCATATATACATAGACAA   8 1102 1042356 N/A N/A 452666 452685 GGCCCCCAAACCCATTTTCT 114 1103 1042388 N/A N/A 453520 453539 AATATTTAAAATATTGTTGG 120 1104 1042420 N/A N/A 454296 454315 CTGCTATAAATCAAAGACAT  74 1105 1042452 N/A N/A 455135 455154 TAGACTTTACAAAGACTATG  46 1106 1042484 N/A N/A 455425 455444 CTGGTGAGCCCCATTCTTTT  39 1107 1042516 N/A N/A 456710 456729 CTGCTATTATCATACAGGAC  18 1108

TABLE 16  Reduction of ATXN1 RNA by 5-10-5 MOE gapmers with mixed PO/PS linkages in A-431 Cells SEQ ID SEQ ID SEQ ID SEQ ID NO: 1 NO: 1 NO: 2 NO: 2 ATXN1 Compound Start Stop Start Stop (% SEQ Number Site Site Site Site Sequence (5′ to 3′) Control) ID NO  994605 N/A N/A  17726  17745 GTCACCTTTTCTATTTGCAC   3  138 1040085   964   983 435683 435702 GTTGGATTTCATTTTTCGCC  21 1109 1040117  2896  2915 457149 457168 ATACTCTACCAAAACTTCAA  90 1110 1040149  3411  3430 457664 457683 CCACGCTGCCTCTACTTGCC  49 1111 1040181  4135  4154 458388 458407 AGCAGAAATGAAATCCCGCA  33 1112 1040213  4588  4607 458841 458860 AGTGAGATACAGTACTTGTT  11 1113 1040245  4889  4908 459142 459161 ACTGGACAAAAATGAGTATT  39 1114 1040277  5326  5345 459579 459598 TGTACCAAACATTAAATCTC  53 1115 1040309  5639  5658 459892 459911 ACGGTTTATAAAAATCATTA  71 1116 1040341  6066  6085 460319 460338 TTGCTCCAAACCATGTGTGT  37 1117 1040373  6641  6660 460894 460913 CCACACTTCCCGTCCAGGCT  19 1118 1040405  7293  7312 461546 461565 CCAACATAGAAAATTATCCT  27 1119 1040437  7702  7721 461955 461974 AAGAGTGGATTTTATGATTA  26 1120 1040469  8177  8196 462430 462449 GGGTTAAAAACAAATGTGGA  67 1121 1040501  8482  8501 462735 462754 AGCTTCTCAAATCAGGTGTA  14 1122 1040533  8732  8751 462985 463004 CTTCCAGGCCATAACCATAC  23 1123 1040565  9179  9198 463432 463451 CTGGCCTCTTTATATTAAAT  83 1124 1040597  9518  9537 463771 463790 GAGTCCTTTCAGATAAGAAA  18 1125 1040629 10046 10065 464299 464318 CTCTGGAGCCAGGACTCCAC 111 1126 1040661 10289 10308 464542 464561 CATATGGAAAAAAGTTCTCC  69 1127 1040693 10566 10585 464819 464838 TGTACTGGTATACAGACAAT  79 1128 1040725 N/A N/A  21690  21709 CCAATAAAAGCCACAACTTG 101 1129 1040757 N/A N/A  34751  34770 AAGGTGTATATTTATATGTT   9 1130 1040789 N/A N/A  56964  56983 GCTCAAATTCAAAAGATGAA  44 1131 1040821 N/A N/A  79281  79300 TCAGTAAAACCTCAATCATT  51 1132 1040853 N/A N/A 100126 100145 TGGAATATTCTTTATTTTGG  68 1133 1040885 N/A N/A 127831 127850 TTACTCTTTCAAATGCAAAA 124 1134 1040917 N/A N/A 157778 157797 AGGTTCTATATTTAGAACAC 143 1135 1040949 N/A N/A 181515 181534 CTCACAATTCAAAAGTTGTG  93 1136 1040981 N/A N/A 203086 203105 TTAGTCAAACATATCAACCT  52 1137 1041013 N/A N/A 218395 218414 GGCTGCAAACTATTCAAGTA  99 1138 1041045 N/A N/A 242013 242032 TCATTATTAGATTACCAAGA  36 1139 1041077 N/A N/A 263601 263620 CAGTAATTTCAAAAGGGCCA 139 1140 1041109 N/A N/A 281523 281542 TGGATGCTATTTTATGTAGA   3 1141 1041141 N/A N/A 304301 304320 GACCACAAAACCCAACTTAC  41 1142 1041173 N/A N/A 329293 329312 TCAACAAATCAAATACTGAT  94 1143 1041205 N/A N/A 350846 350865 TGCTGCATATTTTATATTTA  21 1144 1041237 N/A N/A 375452 375471 AGTGTATTAGATTAGGTCTA   3 1145 1041269 N/A N/A 399227 399246 CTCCTTAAACCCCATTTTAT  79 1146 1041301 N/A N/A 430469 430488 CTCCTAAAAATACATCTTAA 129 1147 1041333 N/A N/A 437958 437977 CCTGGTAAGAAAAAGTGCCG 126 1148 1041365 N/A N/A 438420 438439 GTTTGCCACATTTCCCCTCA  20 1149 1041397 N/A N/A 438974 438993 CAGAGCTAATTCCTAGGAGC  35 1150 1041429 N/A N/A 439254 439273 GCATGTAATCGATCTAAGAA  16 1151 1041461 N/A N/A 439954 439973 TTCAGGGCTAAAAGCTCTCG 113 1152 1041493 N/A N/A 440278 440297 CTGTTCACAAAAATGTGTTA  54 1153 1041525 N/A N/A 440829 440848 TCATTTAATCATTAATTTTG 109 1154 1041557 N/A N/A 441447 441466 GATTTTGCTTATTAAGCTCA  23 1155 1041589 N/A N/A 441816 441835 GTGAGCCAATGATCCCATCA  68 1156 1041621 N/A N/A 442291 442310 TCAGCCCCTTAAAAATCATC 127 1157 1041653 N/A N/A 442874 442893 GGATATGTTCAGACTCAGAT   7 1158 1041685 N/A N/A 443223 443242 CCAGTTCATACTCAGAAATA  61 1159 1041717 N/A N/A 443628 443647 TGGCACTGAATATTAAGCAG  52 1160 1041749 N/A N/A 444026 444045 AGTGTGTATTACCAACAACT  13 1161 1041781 N/A N/A 444482 444501 CTGTATAATAATGTAATGCT   6 1162 1041813 N/A N/A 445369 445388 TCTATTTAAAACACTGAATC  88 1163 1041845 N/A N/A 445681 445700 GGGAGCAATGAATTCTCTCA 111 1164 1041877 N/A N/A 445946 445965 CTACTATATCTAAACACTAT 121 1165 1041909 N/A N/A 446170 446189 TTCCTCCATCCATCCCCCTA 108 1166 1041941 N/A N/A 446742 446761 AGCCCATTTTTTCATCCAGT   7 1167 1041973 N/A N/A 447025 447044 TGTGGCTTTACCGCCTAACA 106 1168 1042005 N/A N/A 447997 448016 TCTCCTCTTTATACCAGGGA  47 1169 1042037 N/A N/A 448611 448630 TATTTTTTTACTACCTCCAC  72 1170 1042069 N/A N/A 448882 448901 AGTGACCACACTATCCGATG  28 1171 1042101 N/A N/A 449428 449447 CTTGAATTTAAAACCCATAT  83 1172 1042133 N/A N/A 449745 449764 TGCACACATCTCAAATAGGT  40 1173 1042165 N/A N/A 450037 450056 TTTGCCTAAATTCTGCCTTT  68 1174 1042197 N/A N/A 450727 450746 CTCACCAACCTCATCTCTCG  98 1175 1042229 N/A N/A 451449 451468 ACAACTAACTATATATTGTT  97 1176 1042261 N/A N/A 451738 451757 GTTTCCCTCTAAAGACTTCA  17 1177 1042293 N/A N/A 452058 452077 GACCAGAAGCCTTAGTTCCA  26 1178 1042325 N/A N/A 452384 452403 ACACAGAAACATATATGTGC  87 1179 1042357 N/A N/A 452669 452688 ATTGGCCCCCAAACCCATTT  83 1180 1042389 N/A N/A 453547 453566 TCTGAATGAATATTGGCTAT  21 1181 1042421 N/A N/A 454309 454328 GATGAGAATTAAACTGCTAT  66 1182 1042453 N/A N/A 455147 455166 GAGTCATACATATAGACTTT 132 1183 1042485 N/A N/A 455452 455471 TCAGGATACACCAAGGGAGG  82 1184 1042517 N/A N/A 456712 456731 AACTGCTATTATCATACAGG  57 1185

TABLE 17  Reduction of ATXN1 RNA by 5-10-5 MOE gapmers with mixed PO/PS linkages in A-431 Cells SEQ ID SEQ ID SEQ ID SEQ ID NO: 1 NO: 1 NO: 2 NO: 2 ATXN1 Compound Start Stop Start Stop (% SEQ Number Site Site Site Site Sequence (5′ to 3′) Control) ID NO  994605 N/A N/A  17726  17745 GTCACCTTTTCTATTTGCAC   3  138 1040086  1112  1131 435831 435850 CCCGGCCACCAGGGTTGCCC 110 1186 1040118  2897  2916 457150 457169 GATACTCTACCAAAACTTCA  64 1187 1040150  3412  3431 457665 457684 CCCACGCTGCCTCTACTTGC  56 1188 1040182  4147  4166 458400 458419 GCACTAGTAAAAAGCAGAAA  72 1189 1040214  4594  4613 458847 458866 GTTTAAAGTGAGATACAGTA  15 1190 1040246  4923  4942 459176 459195 AGGTTCTTTAAAAGTTCATC  12 1191 1040278  5330  5349 459583 459602 GGTTTGTACCAAACATTAAA 106 1192 1040310  5652  5671 459905 459924 TACACCCCAGAAAACGGTTT 124 1193 1040342  6069  6088 460322 460341 CTATTGCTCCAAACCATGTG  39 1194 1040374  6678  6697 460931 460950 ACTGGCCAACACGCTCAGAA 102 1195 1040406  7294  7313 461547 461566 ACCAACATAGAAAATTATCC  30 1196 1040438  7722  7741 461975 461994 AGTAAAGATCAAACTGTGCA  14 1197 1040470  8178  8197 462431 462450 TGGGTTAAAAACAAATGTGG  81 1198 1040502  8484  8503 462737 462756 TCAGCTTCTCAAATCAGGTG  13 1199 1040534  8740  8759 462993 463012 TAGTAATTCTTCCAGGCCAT  23 1200 1040566  9181  9200 463434 463453 TTCTGGCCTCTTTATATTAA  30 1201 1040598  9521  9540 463774 463793 CTTGAGTCCTTTCAGATAAG  28 1202 1040630 10087 10106 464340 464359 TCTGATATTAAAACATCCAG  34 1203 1040662 10290 10309 464543 464562 GCATATGGAAAAAAGTTCTC  24 1204 1040694 10583 10602 464836 464855 TACTGAAACAATAAACTTGT 102 1205 1040726 N/A N/A  22134  22153 TCTTCCTCCTTTTATATCTG  30 1206 1040758 N/A N/A  34802  34821 GGATTAAAAATTATGACCTC  57 1207 1040790 N/A N/A  59689  59708 GGAGCAGTTCCTTAACTATC  20 1208 1040822 N/A N/A  79548  79567 CCCCTTACCCAAACCCTTGG 124 1209 1040854 N/A N/A 102583 102602 AGAGATAATTTTTAATGCAG  34 1210 1040886 N/A N/A 129211 129230 CCATTAAACATTTATTTTGC  11 1211 1040918 N/A N/A 158178 158197 TCTATATTCCCTTAACCGTA  32 1212 1040950 N/A N/A 182959 182978 CATTTTCAACCTTATGATAT  42 1213 1040982 N/A N/A 203492 203511 CAGACATTCCTTTAATATGC  17 1214 1041014 N/A N/A 218412 218431 TAGAACTTTTAAAGCAAGGC  52 1215 1041046 N/A N/A 242061 242080 AGTCAAATAGTCTATCAGTA  11 1216 1041078 N/A N/A 263847 263866 ACATGATTTTAAAAGTCTTA  73 1217 1041110 N/A N/A 281874 281893 TCCCCACACCCTTAAACTGC 115 1218 1041142 N/A N/A 310242 310261 TACACATAAATTTATATCTG  78 1219 1041174 N/A N/A 329490 329509 TGGTTCTATATTTATGTACC  25 1220 1041206 N/A N/A 353449 353468 TTGTCTAAACCTGTTTGAGG   6 1221 1041238 N/A N/A 375665 375684 GCTACCAAAATACAGAACTT  66 1222 1041270 N/A N/A 399709 399728 GCACCATTTTAAAAATGGCT 123 1223 1041302 N/A N/A 430826 430845 TCATCTAAACCTAATACGGC  99 1224 1041334 N/A N/A 437968 437987 TCTGTCTTTTCCTGGTAAGA  11 1225 1041366 N/A N/A 438425 438444 CTGTTGTTTGCCACATTTCC   9 1226 1041398 N/A N/A 438975 438994 CCAGAGCTAATTCCTAGGAG   4 1227 1041430 N/A N/A 439288 439307 TTGGGCAGTGAAAGAAATGG  74 1228 1041462 N/A N/A 439989 440008 ACCTACAGTGACATCTCATA  63 1229 1041494 N/A N/A 440279 440298 TCTGTTCACAAAAATGTGTT  94 1230 1041526 N/A N/A 440834 440853 CTCTTTCATTTAATCATTAA  47 1231 1041558 N/A N/A 441464 441483 TCCCCAATCAAATTTGTGAT  62 1232 1041590 N/A N/A 441897 441916 GTAGTGGTACACACCCATAG  77 1233 1041622 N/A N/A 442320 442339 GGCATCTTTCCACAGTCTTA  43 1234 1041654 N/A N/A 442947 442966 CCGAGCCATCTAAGTTGAAG  30 1235 1041686 N/A N/A 443225 443244 ATCCAGTTCATACTCAGAAA  29 1236 1041718 N/A N/A 443659 443678 CACCCACGCCAGGACAGTCG 128 1237 1041750 N/A N/A 444049 444068 TTCCAGCACCAGAACAGACA 116 1238 1041782 N/A N/A 444483 444502 TCTGTATAATAATGTAATGC  11 1239 1041814 N/A N/A 445371 445390 GTTCTATTTAAAACACTGAA  25 1240 1041846 N/A N/A 445703 445722 CATACAAATTTCGCCTGTTG  55 1241 1041878 N/A N/A 445947 445966 ACTACTATATCTAAACACTA 109 1242 1041910 N/A N/A 446176 446195 TACCCCTTCCTCCATCCATC  88 1243 1041942 N/A N/A 446750 446769 CTCAATATAGCCCATTTTTT  47 1244 1041974 N/A N/A 447063 447082 GACCTCCCCCAGGGAGAGGA  75 1245 1042006 N/A N/A 447998 448017 TTCTCCTCTTTATACCAGGG  12 1246 1042038 N/A N/A 448613 448632 ACTATTTTTTTACTACCTCC  54 1247 1042070 N/A N/A 448885 448904 ACCAGTGACCACACTATCCG  45 1248 1042102 N/A N/A 449429 449448 CCTTGAATTTAAAACCCATA  42 1249 1042134 N/A N/A 449762 449781 GAAAGTTAAAATCTTGTTGC  57 1250 1042166 N/A N/A 450040 450059 CTTTTTGCCTAAATTCTGCC  70 1251 1042198 N/A N/A 450728 450747 TCTCACCAACCTCATCTCTC  77 1252 1042230 N/A N/A 451450 451469 AACAACTAACTATATATTGT 112 1253 1042262 N/A N/A 451767 451786 AGTGCAAAAGTCAGGATACA  12 1254 1042294 N/A N/A 452064 452083 TCAGAAGACCAGAAGCCTTA  62 1255 1042326 N/A N/A 452397 452416 ACATTTACATCACACACAGA 104 1256 1042358 N/A N/A 452685 452704 GGATTTTATCCCAGTCATTG  57 1257 1042390 N/A N/A 453577 453596 GAGGAATGAAAATGGTAGAT  25 1258 1042422 N/A N/A 454311 454330 CAGATGAGAATTAAACTGCT  62 1259 1042454 N/A N/A 455148 455167 AGAGTCATACATATAGACTT 129 1260 1042486 N/A N/A 455459 455478 ATGGAGTTCAGGATACACCA  54 1261 1042518 N/A N/A 456740 456759 GGTCTTAGATTTTATGAGCT  16 1262

TABLE 18  Reduction of ATXN1 RNA by 5-10-5 MOE gapmers with mixed PO/PS linkages in A-431 Cells SEQ ID SEQ ID SEQ ID SEQ ID NO: 1 NO: 1 NO: 2 NO: 2 ATXN1 Compound Start Stop Start Stop (% SEQ Number Site Site Site Site Sequence (5′ to 3′) Control) ID NO  994605 N/A N/A  17726  17745 GTCACCTTTTCTATTTGCAC   3  138 1040087  1115  1134 435834 435853 GGCCCCGGCCACCAGGGTTG 104 1263 1040119  2898  2917 457151 457170 GGATACTCTACCAAAACTTC  20 1264 1040151  3423  3442 457676 457695 GTTTCCTTTCCCCCACGCTG  23 1265 1040183  4148  4167 458401 458420 TGCACTAGTAAAAAGCAGAA  99 1266 1040215  4609  4628 458862 458881 TTTTTTCCCCAAAGAGTTTA  37 1267 1040247  4924  4943 459177 459196 AAGGTTCTTTAAAAGTTCAT  20 1268 1040279  5332  5351 459585 459604 TGGGTTTGTACCAAACATTA  59 1269 1040311  5676  5695 459929 459948 CTAAACCTATTCAAATGTTT  90 1270 1040343  6078  6097 460331 460350 ATGATGTTCCTATTGCTCCA  11 1271 1040375  6750  6769 461003 461022 TCTTCCTATTTGAAGAGAAA  64 1272 1040407  7311  7330 461564 461583 GGGAAAACGAAAAGTTGACC  29 1273 1040439  7724  7743 461977 461996 TCAGTAAAGATCAAACTGTG 103 1274 1040471  8180  8199 462433 462452 TCTGGGTTAAAAACAAATGT  69 1275 1040503  8486  8505 462739 462758 CTTCAGCTTCTCAAATCAGG  26 1276 1040535  8767  8786 463020 463039 ATAGGTATAGTTTAAGAGCC  22 1277 1040567  9195  9214 463448 463467 ATGCTCCGTATTTATTCTGG   9 1278 1040599  9523  9542 463776 463795 GACTTGAGTCCTTTCAGATA  32 1279 1040631 10088 10107 464341 464360 ATCTGATATTAAAACATCCA  33 1280 1040663 10327 10346 464580 464599 TACAATATTTTACACTGGAA  11 1281 1040695 10609 10628 464862 464881 GCACTGTTATTTTATTAGTA  41 1282 1040727 N/A N/A  22675  22694 CTGTGGTTTTAAAGGCTGTA   4 1283 1040759 N/A N/A  34869  34888 GGTTTTAAAAACATCCTCCT  41 1284 1040791 N/A N/A  63051  63070 TTTTAGCACCTTTAAACTCT  85 1285 1040823 N/A N/A  79759  79778 CTCTCATTTTAAAGTTTTCT  44 1286 1040855 N/A N/A 103256 103275 ATCTTTATTCAAAAATGCAA  88 1287 1040887 N/A N/A 132848 132867 TTCATGTTTTAAAGCTGAGA  11 1288 1040919 N/A N/A 158451 158470 CTCACAATTCAAAATTATTC  44 1289 1040951 N/A N/A 182994 183013 AACCTTAGAAATGTACATTT  29 1290 1040983 N/A N/A 204258 204277 CTAGCAATTCAAAACAATAT  45 1291 1041015 N/A N/A 219043 219062 CTTCTCCTTCCTTAATAGAT  65 1292 1041047 N/A N/A 243398 243417 TCTCAAGGCCCTTAATTGCC  67 1293 1041079 N/A N/A 264140 264159 ACTTTTAAATCCCCCTAAAG 105 1294 1041111 N/A N/A 281939 281958 CTCACATTTCTTTATACACA   2 1295 1041143 N/A N/A 311352 311371 GTGAGATTTTAAAGACATTC   1 1296 1041175 N/A N/A 330016 330035 GATGCCAAACTATTATCTCA   7 1297 1041207 N/A N/A 354249 354268 AGACAATTTTAAAAGCTTCC   8 1298 1041239 N/A N/A 375816 375835 TCTCTTAACCAAAGAATCTG 132 1299 1041271 N/A N/A 400962 400981 ATGCTGTTCCTTTATAACGG  16 1300 1041303 N/A N/A 431185 431204 AATTTCTAAATTTAGCCCAG  55 1301 1041335 N/A N/A 437990 438009 TCCCCTCACTCCAACGGCAT  80 1302 1041367 N/A N/A 438448 438467 CTCCCATGAAACCACAATAA 142 1303 1041399 N/A N/A 439002 439021 CTGACTTTTATATGCAAACC  25 1304 1041431 N/A N/A 439344 439363 CTCGATAGCCAGGAAAGCTC  64 1305 1041463 N/A N/A 439996 440015 ACTGTAAACCTACAGTGACA 130 1306 1041495 N/A N/A 440280 440299 CTCTGTTCACAAAAATGTGT  95 1307 1041527 N/A N/A 440836 440855 TTCTCTTTCATTTAATCATT  16 1308 1041559 N/A N/A 441465 441484 TTCCCCAATCAAATTTGTGA  83 1309 1041591 N/A N/A 442071 442090 GAGATTATCTCCTATGAAGA  50 1310 1041623 N/A N/A 442374 442393 AGCATTTTTCTCCTACATTG  14 1311 1041655 N/A N/A 442950 442969 GGCCCGAGCCATCTAAGTTG 129 1312 1041687 N/A N/A 443226 443245 AATCCAGTTCATACTCAGAA  47 1313 1041719 N/A N/A 443664 443683 ACTCACACCCACGCCAGGAC 109 1314 1041751 N/A N/A 444094 444113 CCACAAACAAAAATGTGGTT  79 1315 1041783 N/A N/A 444487 444506 CTGTTCTGTATAATAATGTA  48 1316 1041815 N/A N/A 445372 445391 TGTTCTATTTAAAACACTGA  62 1317 1041847 N/A N/A 445705 445724 GACATACAAATTTCGCCTGT  22 1318 1041879 N/A N/A 445948 445967 AACTACTATATCTAAACACT  95 1319 1041911 N/A N/A 446181 446200 CTGCCTACCCCTTCCTCCAT  80 1320 1041943 N/A N/A 446755 446774 GACAGCTCAATATAGCCCAT  28 1321 1041975 N/A N/A 447085 447104 AGCCAGAACTAAAGTGGGCT  74 1322 1042007 N/A N/A 448000 448019 CCTTCTCCTCTTTATACCAG  35 1323 1042039 N/A N/A 448615 448634 ATACTATTTTTTTACTACCT  65 1324 1042071 N/A N/A 448888 448907 GACACCAGTGACCACACTAT  46 1325 1042103 N/A N/A 449430 449449 TCCTTGAATTTAAAACCCAT  55 1326 1042135 N/A N/A 449763 449782 TGAAAGTTAAAATCTTGTTG  75 1327 1042167 N/A N/A 450041 450060 TCTTTTTGCCTAAATTCTGC  43 1328 1042199 N/A N/A 450731 450750 TCCTCTCACCAACCTCATCT  77 1329 1042231 N/A N/A 451490 451509 CTTTTAGAAACTAACTCTGG 107 1330 1042263 N/A N/A 451782 451801 GTACTATAATTGATTAGTGC  50 1331 1042295 N/A N/A 452071 452090 GTGACATTCAGAAGACCAGA  15 1332 1042327 N/A N/A 452400 452419 ACTACATTTACATCACACAC  83 1333 1042359 N/A N/A 452688 452707 TTAGGATTTTATCCCAGTCA  28 1334 1042391 N/A N/A 453658 453677 GCATTATAGAAAATACTAAA  85 1335 1042423 N/A N/A 454312 454331 GCAGATGAGAATTAAACTGC 100 1336 1042455 N/A N/A 455154 455173 TCATATAGAGTCATACATAT  45 1337 1042487 N/A N/A 455532 455551 TGAACATTCCAAAGTGGAGC  44 1338 1042519 N/A N/A 456742 456761 GCGGTCTTAGATTTTATGAG  24 1339

TABLE 19  Reduction of ATXN1 RNA by 5-10-5 MOE gapmers with mixed PO/PS linkages in A-431 Cells SEQ ID SEQ ID SEQ ID SEQ ID NO: 1 NO: 1 NO: 2 NO: 2 ATXN1 Compound Start Stop Start Stop (% SEQ Number Site Site Site Site Sequence (5′ to 3′) Control) ID NO  994605 N/A N/A  17726  17745 GTCACCTTTTCTATTTGCAC   3  138 1040088  1144  1163 435863 435882 CCCTGCCGGCCCATGCCTCC 159 1340 1040120  2908  2927 457161 457180 CACAAAAAAAGGATACTCTA 104 1341 1040152  3453  3472 457706 457725 ATCTGGATACAAATGATAAG  50 1342 1040184  4176  4195 458429 458448 GTCCACCACAACACCCTGGT  78 1343 1040216  4671  4690 458924 458943 CAGAGCTGAAATGTAGTTAC  12 1344 1040248  4926  4945 459179 459198 GCAAGGTTCTTTAAAAGTTC  11 1345 1040280  5347  5366 459600 459619 ATGAAATACCCTTTCTGGGT 124 1346 1040312  5684  5703 459937 459956 TAGCTATTCTAAACCTATTC 140 1347 1040344  6080  6099 460333 460352 TGATGATGTTCCTATTGCTC  15 1348 1040376  6870  6889 461123 461142 GAAGAATTTCTACCCCTGTC  39 1349 1040408  7336  7355 461589 461608 ATCCCAAACTAAACTGGGTG 105 1350 1040440  7732  7751 461985 462004 AACATATTTCAGTAAAGATC  13 1351 1040472  8194  8213 462447 462466 TCTATTTCAGAAATTCTGGG  11 1352 1040504  8505  8524 462758 462777 TGCTTCAAAATTTTGTTTTC  40 1353 1040536  8815  8834 463068 463087 TTCCCCTCCCTCAGACGAGG 109 1354 1040568  9206  9225 463459 463478 ATTCTGAGAAGATGCTCCGT  35 1355 1040600  9525  9544 463778 463797 AAGACTTGAGTCCTTTCAGA  26 1356 1040632 10089 10108 464342 464361 GATCTGATATTAAAACATCC  20 1357 1040664 10329 10348 464582 464601 AGTACAATATTTTACACTGG  14 1358 1040696 N/A N/A   5825   5844 GTCAAGTTTTAAAATGTGAC  68 1359 1040728 N/A N/A  22774  22793 ACTGAAACAATTTATCTAAG  83 1360 1040760 N/A N/A  36098  36117 ACAAAAATAATTTAAGCCAC 106 1361 1040792 N/A N/A  63073  63092 TACTATCACCTTTAAACTTT  71 1362 1040824 N/A N/A  80953  80972 ACCGCCAAAACCAACCAGGG  65 1363 1040856 N/A N/A 103405 103424 CTAATCTATCAAATAAAGGA 105 1364 1040888 N/A N/A 133117 133136 GAGAGGTTTCATTATGTAAA   5 1365 1040920 N/A N/A 158507 158526 GCACTTAGACAATGCTGCAG 106 1366 1040952 N/A N/A 183278 183297 GGTAAGTTATTTTAAAACTT  76 1367 1040984 N/A N/A 205648 205667 AGTTTTACGATATATGAATC  81 1368 1041016 N/A N/A 219199 219218 TACCATTATTTTTAGCTTTT  18 1369 1041048 N/A N/A 243460 243479 CAGTTTATTCTTTACCCAAA  10 1370 1041080 N/A N/A 264569 264588 CCCACATTTTAAAGATGCAG  46 1371 1041112 N/A N/A 282392 282411 TCCAGAAACCTTTATTATTG   1 1372 1041144 N/A N/A 311667 311686 AACAGGTTACAAATACGGTT   1 1373 1041176 N/A N/A 330322 330341 ATTCTGTTTTAAATTCCTTT   1 1374 1041208 N/A N/A 354293 354312 ATGCAATTTCAAAAGCTGGC  10 1375 1041240 N/A N/A 376063 376082 GTGGATACTTTTTAAAACTC   2 1376 1041272 N/A N/A 401167 401186 GTCGCAAACCTTTATGGAGT   6 1377 1041304 N/A N/A 431998 432017 CAAATCCAAATTTATTCTTC  76 1378 1041336 N/A N/A 437997 438016 CATCTAATCCCCTCACTCCA  92 1379 1041368 N/A N/A 438450 438469 GCCTCCCATGAAACCACAAT 122 1380 1041400 N/A N/A 439003 439022 CCTGACTTTTATATGCAAAC  11 1381 1041432 N/A N/A 439351 439370 AAGTACGCTCGATAGCCAGG  22 1382 1041464 N/A N/A 439999 440018 AAGACTGTAAACCTACAGTG 101 1383 1041496 N/A N/A 440281 440300 CCTCTGTTCACAAAAATGTG 121 1384 1041528 N/A N/A 440838 440857 ATTTCTCTTTCATTTAATCA  33 1385 1041560 N/A N/A 441466 441485 CTTCCCCAATCAAATTTGTG  87 1386 1041592 N/A N/A 442072 442091 AGAGATTATCTCCTATGAAG  70 1387 1041624 N/A N/A 442397 442416 AGGGATAGTGACAAACACGG   8 1388 1041656 N/A N/A 442952 442971 AGGGCCCGAGCCATCTAAGT 122 1389 1041688 N/A N/A 443233 443252 CCCCTCAAATCCAGTTCATA 111 1390 1041720 N/A N/A 443705 443724 CATCATGATAACAACTGCTG  47 1391 1041752 N/A N/A 444095 444114 CCCACAAACAAAAATGTGGT 100 1392 1041784 N/A N/A 444575 444594 GAGTAAAATGATCAGTGGGT  15 1393 1041816 N/A N/A 445373 445392 GTGTTCTATTTAAAACACTG 107 1394 1041848 N/A N/A 445706 445725 AGACATACAAATTTCGCCTG  45 1395 1041880 N/A N/A 445954 445973 GTCAATAACTACTATATCTA  54 1396 1041912 N/A N/A 446182 446201 TCTGCCTACCCCTTCCTCCA  61 1397 1041944 N/A N/A 446788 446807 CCACAGATAACCAAAGCACG  37 1398 1041976 N/A N/A 447087 447106 CCAGCCAGAACTAAAGTGGG  75 1399 1042008 N/A N/A 448004 448023 GGCCCCTTCTCCTCTTTATA 118 1400 1042040 N/A N/A 448617 448636 TGATACTATTTTTTTACTAC  97 1401 1042072 N/A N/A 448922 448941 GAGACAGAACATACACGCAA  35 1402 1042104 N/A N/A 449432 449451 ATTCCTTGAATTTAAAACCC  51 1403 1042136 N/A N/A 449764 449783 GTGAAAGTTAAAATCTTGTT  47 1404 1042168 N/A N/A 450045 450064 TGTTTCTTTTTGCCTAAATT  13 1405 1042200 N/A N/A 450734 450753 TTTTCCTCTCACCAACCTCA  67 1406 1042232 N/A N/A 451491 451510 ACTTTTAGAAACTAACTCTG  71 1407 1042264 N/A N/A 451796 451815 GCCCTTTATAACAGGTACTA  44 1408 1042296 N/A N/A 452072 452091 TGTGACATTCAGAAGACCAG  27 1409 1042328 N/A N/A 452405 452424 TCAAAACTACATTTACATCA 118 1410 1042360 N/A N/A 452691 452710 GGTTTAGGATTTTATCCCAG  25 1411 1042392 N/A N/A 453659 453678 TGCATTATAGAAAATACTAA 121 1412 1042424 N/A N/A 454313 454332 GGCAGATGAGAATTAAACTG  38 1413 1042456 N/A N/A 455163 455182 CAGGGCTTCTCATATAGAGT  31 1414 1042488 N/A N/A 455538 455557 GGCACTTGAACATTCCAAAG  10 1415 1042520 N/A N/A 456757 456776 GCTCACAAGCCCAGCGCGGT  90 1416

TABLE 20  Reduction of ATXN1 RNA by 5-10-5 MOE gapmers with mixed PO/PS linkages in A-431 Cells SEQ ID SEQ ID SEQ ID SEQ ID NO: 1 NO: 1 NO: 2 NO: 2 ATXN1 Compound Start Stop Start Stop (% SEQ Number Site Site Site Site Sequence (5′ to 3′) Control) ID NO  994605 N/A N/A  17726  17745 GTCACCTTTTCTATTTGCAC   3  138 1040089  1170  1189 435889 435908 TGTTGTAAACCAAGCTCCAC  56 1417 1040121  2915  2934 457168 457187 GTCCAAACACAAAAAAAGGA  90 1418 1040153  3475  3494 457728 457747 TATTTTAGCCTACAGTACAG  70 1419 1040185  4179  4198 458432 458451 CCTGTCCACCACAACACCCT  80 1420 1040217  4683  4702 458936 458955 TCAGCAATTCTGCAGAGCTG 103 1421 1040249  4953  4972 459206 459225 AAGTTATAAACTCAATATGT  38 1422 1040281  5348  5367 459601 459620 TATGAAATACCCTTTCTGGG 106 1423 1040313  5686  5705 459939 459958 TCTAGCTATTCTAAACCTAT  80 1424 1040345  6092  6111 460345 460364 CCACAAAAATTATGATGATG  45 1425 1040377  6871  6890 461124 461143 CGAAGAATTTCTACCCCTGT  47 1426 1040409  7338  7357 461591 461610 TCATCCCAAACTAAACTGGG  87 1427 1040441  7734  7753 461987 462006 GCAACATATTTCAGTAAAGA  13 1428 1040473  8203  8222 462456 462475 CTTAAATTCTCTATTTCAGA  30 1429 1040505  8506  8525 462759 462778 GTGCTTCAAAATTTTGTTTT  27 1430 1040537  8821  8840 463074 463093 ACCGAGTTCCCCTCCCTCAG 106 1431 1040569  9217  9236 463470 463489 ACAGGAATACTATTCTGAGA  38 1432 1040601  9550  9569 463803 463822 GAAGCCTCCAATGTATCTGC  17 1433 1040633 10134 10153 464387 464406 GGTGTCTGTTTTCCCTTGGC  14 1434 1040665 10330 10349 464583 464602 AAGTACAATATTTTACACTG  20 1435 1040697 N/A N/A   6321   6340 GGCCATAAAATTGTAAACTG  44 1436 1040729 N/A N/A  23146  23165 AACATCTAAATTTATAATGA 113 1437 1040761 N/A N/A  36881  36900 AGGTGGTTACAAACATAAAT  35 1438 1040793 N/A N/A  63098  63117 AGCTAAAAACCCAACATGGG  81 1439 1040825 N/A N/A  81039  81058 GACAGTTATTTTTAAGAGGC   7 1440 1040857 N/A N/A 103451 103470 TTGGACTTTTAAATGTAAGT  83 1441 1040889 N/A N/A 135046 135065 TGTGTCTAAATTTATGGTAG  13 1442 1040921 N/A N/A 160360 160379 GTTGAATTTCAAAAATCAAA  59 1443 1040953 N/A N/A 184290 184309 CAGGAAAAAATACAGGGTGT  19 1444 1040985 N/A N/A 206209 206228 ACCTAAAAAAATATAGATCC 142  1445 1041017 N/A N/A 223097 223116 CTAATTAATCCTTAAATTGC 109 1446 1041049 N/A N/A 244961 244980 TTTCAATATATTTACACACT  63 1447 1041081 N/A N/A 266459 266478 CTCACACAAATTTACATTCT  89 1448 1041113 N/A N/A 284256 284275 ACCTAAAAAATACATCTTTA  94 1449 1041145 N/A N/A 313344 313363 CTGAAGATTCCTTAATATCT   1 1450 1041177 N/A N/A 331091 331110 CTAATGTTTTAAAACTCTTG  35 1451 1041209 N/A N/A 355246 355265 TTCCAATTTTAAAAAACCTG  44 1452 1041241 N/A N/A 376190 376209 CTGTCAAAAATATAATACCT  81 1453 1041273 N/A N/A 401168 401187 TGTCGCAAACCTTTATGGAG  33 1454 1041305 N/A N/A 432296 432315 AAGTCCTTTCAAAGCCAAGT  38 1455 1041337 N/A N/A 437999 438018 AGCATCTAATCCCCTCACTC  42 1456 1041369 N/A N/A 438464 438483 AACCCGTTTACCCTGCCTCC  77 1457 1041401 N/A N/A 439004 439023 GCCTGACTTTTATATGCAAA  13 1458 1041433 N/A N/A 439362 439381 ACACTTGTAGAAAGTACGCT   8 1459 1041465 N/A N/A 440005 440024 CTTCCAAAGACTGTAAACCT  65 1460 1041497 N/A N/A 440282 440301 GCCTCTGTTCACAAAAATGT  99 1461 1041529 N/A N/A 440844 440863 AAGCCAATTTCTCTTTCATT  57 1462 1041561 N/A N/A 441471 441490 CACAACTTCCCCAATCAAAT  70 1463 1041593 N/A N/A 442076 442095 CTCAAGAGATTATCTCCTAT  30 1464 1041625 N/A N/A 442399 442418 ACAGGGATAGTGACAAACAC  24 1465 1041657 N/A N/A 442969 442988 CTGTGAATCACTTTCTCAGG  73 1466 1041689 N/A N/A 443234 443253 ACCCCTCAAATCCAGTTCAT 129 1467 1041721 N/A N/A 443723 443742 GTAGACAGCCAGTAAGTACA  62 1468 1041753 N/A N/A 444096 444115 ACCCACAAACAAAAATGTGG 132 1469 1041785 N/A N/A 444648 444667 CGCCAATGTGAAAAGGCGAC 1470 1041817 N/A N/A 445374 445393 AGTGTTCTATTTAAAACACT 131 1471 1041849 N/A N/A 445708 445727 CCAGACATACAAATTTCGCC  40 1472 1041881 N/A N/A 445955 445974 AGTCAATAACTACTATATCT  46 1473 1041913 N/A N/A 446221 446240 CCAGCAAGCCCATGTGCTCA 109 1474 1041945 N/A N/A 446792 446811 AGTACCACAGATAACCAAAG  52 1475 1041977 N/A N/A 447180 447199 CTGTATGGAAAAACATTGCA  29 1476 1042009 N/A N/A 448133 448152 ATGATGATCATTATGTAGAG  24 1477 1042041 N/A N/A 448619 448638 AATGATACTATTTTTTTACT  77 1478 1042073 N/A N/A 448923 448942 GGAGACAGAACATACACGCA  44 1479 1042105 N/A N/A 449439 449458 TCTGTGAATTCCTTGAATTT  41 1480 1042137 N/A N/A 449765 449784 GGTGAAAGTTAAAATCTTGT  60 1481 1042169 N/A N/A 450072 450091 TCTTTAATCACTTCAAAGGC  54 1482 1042201 N/A N/A 450754 450773 GGCTTTCCCAATAAACCTGC  37 1483 1042233 N/A N/A 451493 451512 GTACTTTTAGAAACTAACTC  47 1484 1042265 N/A N/A 451798 451817 AAGCCCTTTATAACAGGTAC  38 1485 1042297 N/A N/A 452094 452113 GCCCAACACCAGGCAGAGGT  82 1486 1042329 N/A N/A 452407 452426 TTTCAAAACTACATTTACAT 117 1487 1042361 N/A N/A 452759 452778 TTGTAAATTTTACGAATAGT  63 1488 1042393 N/A N/A 453673 453692 ACCATCAACAGATCTGCATT  62 1489 1042425 N/A N/A 454359 454378 GCCTAGCCCCAAACAGGAAA 117 1490 1042457 N/A N/A 455172 455191 AGGATGCACCAGGGCTTCTC  79 1491 1042489 N/A N/A 455557 455576 GGGCCTGTTTTCTCCTGAAG 116 1492 1042521 N/A N/A 456758 456777 GGCTCACAAGCCCAGCGCGG 132 1493

TABLE 21  Reduction of ATXN1 RNA by 5-10-5 MOE gapmers with mixed PO/PS linkages in A-431 Cells SEQ ID SEQ ID SEQ ID SEQ ID NO: 1 NO: 1 NO: 2 NO: 2 ATXN1 Compound Start Stop Start Stop (% SEQ Number Site Site Site Site Sequence (5′ to 3′) Control) ID NO  994605 N/A N/A  17726  17745 GTCACCTTTTCTATTTGCAC   3  138 1040090  1171  1190 435890 435909 CTGTTGTAAACCAAGCTCCA  64 1494 1040122  2927  2946 457180 457199 ATGACCAGCCCTGTCCAAAC  73 1495 1040154  3482  3501 457735 457754 ACTGTGTTATTTTAGCCTAC  11 1496 1040186  4224  4243 458477 458496 CCCAACCCCCCTTACCCCAT  82 1497 1040218  4709  4728 458962 458981 CATTGAAACTTTCAATATCT  43 1498 1040250  4967  4986 459220 459239 CAGGAATATCACACAAGTTA  17 1499 1040282  5349  5368 459602 459621 CTATGAAATACCCTTTCTGG  79 1500 1040314  5687  5706 459940 459959 TTCTAGCTATTCTAAACCTA  75 1501 1040346  6094  6113 460347 460366 AACCACAAAAATTATGATGA  59 1502 1040378  6872  6891 461125 461144 CCGAAGAATTTCTACCCCTG  31 1503 1040410  7339  7358 461592 461611 ATCATCCCAAACTAAACTGG  71 1504 1040442  7739  7758 461992 462011 TTTTGGCAACATATTTCAGT  16 1505 1040474  8207  8226 462460 462479 TGTTCTTAAATTCTCTATTT  18 1506 1040506  8508  8527 462761 462780 GAGTGCTTCAAAATTTTGTT  20 1507 1040538  8843  8862 463096 463115 CAGTATTCTCAAATCGCAGA  58 1508 1040570  9219  9238 463472 463491 GGACAGGAATACTATTCTGA  45 1509 1040602  9554  9573 463807 463826 GGGTGAAGCCTCCAATGTAT  29 1510 1040634 10151 10170 464404 464423 CCCTCAACCCAAGTTCTGGT  78 1511 1040666 10332 10351 464585 464604 GCAAGTACAATATTTTACAC  13 1512 1040698 N/A N/A   6643   6662 CACTGAAAAATATATGTTCA  28 1513 1040730 N/A N/A  23318  23337 CACTATAAAAACATCTAACA  98 1514 1040762 N/A N/A  38292  38311 TTCAACAATATTTATGCCCA   5 1515 1040794 N/A N/A  63099  63118 CAGCTAAAAACCCAACATGG 109 1516 1040826 N/A N/A  81067  81086 AGTTATATATTTTAGCTGAA  58 1517 1040858 N/A N/A 103630 103649 GCTATATTTTAAAAAGGATC  89 1518 1040890 N/A N/A 137052 137071 CTTTCATTTCAAACTTACTG  59 1519 1040922 N/A N/A 161567 161586 ACTTTCTTTTAAATTCTAAC  69 1520 1040954 N/A N/A 184602 184621 GATGGTAATTTTTAGAGGTG   4 1521 1040986 N/A N/A 206522 206541 TCTTTCTATATTTATCTATA  51 1522 1041018 N/A N/A 223242 223261 GTTTACAAAATATTTGCACA  37 1523 1041050 N/A N/A 245286 245305 TCTATCAAACCTAATCTATC  53 1524 1041082 N/A N/A 267260 267279 AAGGAATTTCTTTACACCAT  27 1525 1041114 N/A N/A 284274 284293 GCACTTCGAATTTATACCAC   2 1526 1041146 N/A N/A 314135 314154 AACATAAAAAATATACCTAA 109 1527 1041178 N/A N/A 331394 331413 GCTGTTAAAATATGCTTTCC   2 1528 1041210 N/A N/A 356766 356785 GGGCACTACCCTTATCTTAA  38 1529 1041242 N/A N/A 376191 376210 CCTGTCAAAAATATAATACC  89 1530 1041274 N/A N/A 402544 402563 CCTTTAAAAATATGCCTTTT  46 1531 1041306 N/A N/A 432451 432470 CCAATAAAACCCCACAGGGT 109 1532 1041338 N/A N/A 438003 438022 CTTTAGCATCTAATCCCCTC  59 1533 1041370 N/A N/A 438465 438484 AAACCCGTTTACCCTGCCTC  76 1534 1041402 N/A N/A 439005 439024 GGCCTGACTTTTATATGCAA 117 1535 1041434 N/A N/A 439383 439402 GTTTTCAAATCCTAGATGGA  26 1536 1041466 N/A N/A 440010 440029 GGGCCCTTCCAAAGACTGTA 124 1537 1041498 N/A N/A 440298 440317 ACCTCTTTTCACACCTGCCT  22 1538 1041530 N/A N/A 440851 440870 CACAGGGAAGCCAATTTCTC  76 1539 1041562 N/A N/A 441483 441502 CATCTCTTCTTCCACAACTT  52 1540 1041594 N/A N/A 442078 442097 CTCTCAAGAGATTATCTCCT 104 1541 1041626 N/A N/A 442489 442508 CTTTCCTCCCACAGCACCTA  49 1542 1041658 N/A N/A 442983 443002 GATTTATTTTTCAGCTGTGA   6 1543 1041690 N/A N/A 443237 443256 TGCACCCCTCAAATCCAGTT  99 1544 1041722 N/A N/A 443729 443748 CCATCGGTAGACAGCCAGTA  39 1545 1041754 N/A N/A 444105 444124 GGTACAAAGACCCACAAACA  51 1546 1041786 N/A N/A 444737 444756 AACATAATATTCAGTGCTAA  40 1547 1041818 N/A N/A 445375 445394 GAGTGTTCTATTTAAAACAC  82 1548 1041850 N/A N/A 445710 445729 TCCCAGACATACAAATTTCG  90 1549 1041882 N/A N/A 445956 445975 TAGTCAATAACTACTATATC 148 1550 1041914 N/A N/A 446222 446241 GCCAGCAAGCCCATGTGCTC 121 1551 1041946 N/A N/A 446793 446812 CAGTACCACAGATAACCAAA  30 1552 1041978 N/A N/A 447541 447560 GCTCAGTTAAAATCTGAAAG  38 1553 1042010 N/A N/A 448228 448247 GTGGGCTCAAGATATCTTCC 113 1554 1042042 N/A N/A 448621 448640 AGAATGATACTATTTTTTTA  92 1555 1042074 N/A N/A 448934 448953 GCCTCCCACCAGGAGACAGA 115 1556 1042106 N/A N/A 449466 449485 GATGTCATCTTCAACTGGAA  28 1557 1042138 N/A N/A 449771 449790 TTCTTTGGTGAAAGTTAAAA  91 1558 1042170 N/A N/A 450076 450095 TTCTTCTTTAATCACTTCAA  35 1559 1042202 N/A N/A 450757 450776 TCTGGCTTTCCCAATAAACC  62 1560 1042234 N/A N/A 451505 451524 AACAACAATCATGTACTTTT  36 1561 1042266 N/A N/A 451800 451819 ACAAGCCCTTTATAACAGGT  16 1562 1042298 N/A N/A 452096 452115 TTGCCCAACACCAGGCAGAG 104 1563 1042330 N/A N/A 452408 452427 GTTTCAAAACTACATTTACA 100 1564 1042362 N/A N/A 452769 452788 TCTTCCAATTTTGTAAATTT  35 1565 1042394 N/A N/A 453674 453693 CACCATCAACAGATCTGCAT  88 1566 1042426 N/A N/A 454361 454380 AGGCCTAGCCCCAAACAGGA 145 1567 1042458 N/A N/A 455185 455204 CAGATCTTAAAAAAGGATGC  59 1568 1042490 N/A N/A 455600 455619 ATCAGGAAAAGATGATGGCC 111 1569 1042522 N/A N/A 456802 456821 AGAGCACCCACTTAGCTTTC  98 1570

TABLE 22  Reduction of ATXN1 RNA by 5-10-5 MOE gapmers with mixed PO/PS linkages in A-431 Cells SEQ ID SEQ ID SEQ ID SEQ ID NO: 1 NO: 1 NO: 2 NO: 2 ATXN1 Compound Start Stop Start Stop (% SEQ Number Site Site Site Site Sequence (5′ to 3′) Control) ID NO  994605 N/A N/A  17726  17745 GTCACCTTTTCTATTTGCAC   2  138 1040091  1181  1200 435900 435919 AACCTATTCCCTGTTGTAAA  23 1571 1040123  2969  2988 457222 457241 ACGGCAAATCAAAGAGCTGG 130 1572 1040155  3517  3536 457770 457789 ACAGAAACCTAAAATTAAGA 116 1573 1040187  4227  4246 458480 458499 ACCCCCAACCCCCCTTACCC 102 1574 1040219  4720  4739 458973 458992 CCTTTAAACCACATTGAAAC  69 1575 1040251  4968  4987 459221 459240 GCAGGAATATCACACAAGTT  14 1576 1040283  5351  5370 459604 459623 AACTATGAAATACCCTTTCT 130 1577 1040315  5696  5715 459949 459968 AAGGAACTATTCTAGCTATT  43 1578 1040347  6097  6116 460350 460369 TAGAACCACAAAAATTATGA  65 1579 1040379  6873  6892 461126 461145 ACCGAAGAATTTCTACCCCT  37 1580 1040411  7351  7370 461604 461623 AACAGAAATCAAATCATCCC  58 1581 1040443  7751  7770 462004 462023 AACAAAAATAAATTTTGGCA 103 1582 1040475  8210  8229 462463 462482 ATGTGTTCTTAAATTCTCTA   9 1583 1040507  8523  8542 462776 462795 TGTACTCCTCAAAGTGAGTG 126 1584 1040539  8844  8863 463097 463116 ACAGTATTCTCAAATCGCAG  67 1585 1040571  9251  9270 463504 463523 CTGTCCAGTTTCCACTGTCC  31 1586 1040603  9584  9603 463837 463856 CAGCAAACAAACTAAAGGGA  29 1587 1040635 10152 10171 464405 464424 GCCCTCAACCCAAGTTCTGG 129 1588 1040667 10375 10394 464628 464647 TATGAATTCTTCCATTTTTT  92 1589 1040699 N/A N/A   7015   7034 AACATTATTCAAAGAAATGT 108 1590 1040731 N/A N/A  24365  24384 AGGCAGAACATTTAACATCG  29 1591 1040763 N/A N/A  38732  38751 TCTGTGTTTATTTAGGTTTC   3 1592 1040795 N/A N/A  64787  64806 ACTGCATTTCAAAACCTACA  25 1593 1040827 N/A N/A  81310  81329 TTGAAGTTTTAAAGTACATG  87 1594 1040859 N/A N/A 105462 105481 ATGTTTAAAATATGCATGCC 152 1595 1040891 N/A N/A 137270 137289 TTTCTCAGAATATAACTGTA  44 1596 1040923 N/A N/A 162773 162792 GTGTAATTTCAAAATAGGGT  10 1597 1040955 N/A N/A 185622 185641 AGCTTTCAAATTTATCCACT   9 1598 1040987 N/A N/A 207222 207241 ACTTAGCCAATTTAACTGCA  26 1599 1041019 N/A N/A 224367 224386 TCTTTAAAACTATTAGTCAC  81 1600 1041051 N/A N/A 245290 245309 CTAATCTATCAAACCTAATC 142 1601 1041083 N/A N/A 267301 267320 TCAGTTAAAATACCTGATGA  94 1602 1041115 N/A N/A 284506 284525 GGTTAATATTTTTATGGTAT   1 1603 1041147 N/A N/A 314443 314462 GTTATAATTTAAAAAGTGTT 100 1604 1041179 N/A N/A 332631 332650 CCGTTTTATTTTTAAACTCG   9 1605 1041211 N/A N/A 356791 356810 GCTTCATTTTAAAAGATTGT   7 1606 1041243 N/A N/A 376226 376245 CCACATAAAATATCGAATCA  40 1607 1041275 N/A N/A 407589 407608 CAGGGCTGTATTTAATTCTG  14 1608 1041307 N/A N/A 433208 433227 GTTCTCAATCCTTAATGATT  55 1609 1041339 N/A N/A 438044 438063 GACATATTTTAAAACATGGA  13 1610 1041371 N/A N/A 438475 438494 AACCAATCCTAAACCCGTTT  62 1611 1041403 N/A N/A 439006 439025 AGGCCTGACTTTTATATGCA 137 1612 1041435 N/A N/A 439384 439403 TGTTTTCAAATCCTAGATGG  43 1613 1041467 N/A N/A 440042 440061 TTTTAAATAAGATCTTTGGG  62 1614 1041499 N/A N/A 440299 440318 AACCTCTTTTCACACCTGCC  26 1615 1041531 N/A N/A 440909 440928 AGTAGAGAGATTTAGTGATC  16 1616 1041563 N/A N/A 441492 441511 GGAGAAAACCATCTCTTCTT  76 1617 1041595 N/A N/A 442096 442115 GCATTAAAAAACGGAACCCT 103 1618 1041627 N/A N/A 442494 442513 TTCCCCTTTCCTCCCACAGC  99 1619 1041659 N/A N/A 442984 443003 TGATTTATTTTTCAGCTGTG   5 1620 1041691 N/A N/A 443239 443258 AATGCACCCCTCAAATCCAG 109 1621 1041723 N/A N/A 443762 443781 AGTCAACCAAAAAATAGTAG  40 1622 1041755 N/A N/A 444110 444129 AGAGAGGTACAAAGACCCAC  52 1623 1041787 N/A N/A 444740 444759 AACAACATAATATTCAGTGC  27 1624 1041819 N/A N/A 445394 445413 TGAGTGTAAGAATCTCTGTG 119 1625 1041851 N/A N/A 445716 445735 ACACTATCCCAGACATACAA  57 1626 1041883 N/A N/A 445961 445980 CCACTTAGTCAATAACTACT  34 1627 1041915 N/A N/A 446223 446242 TGCCAGCAAGCCCATGTGCT  98 1628 1041947 N/A N/A 446796 446815 GAGCAGTACCACAGATAACC  22 1629 1041979 N/A N/A 447542 447561 TGCTCAGTTAAAATCTGAAA  49 1630 1042011 N/A N/A 448333 448352 CTCTAGTTTCCATAGCTTCC  42 1631 1042043 N/A N/A 448635 448654 TTCCAAATACACCTAGAATG  68 1632 1042075 N/A N/A 448937 448956 CTTGCCTCCCACCAGGAGAC 100 1633 1042107 N/A N/A 449467 449486 TGATGTCATCTTCAACTGGA  27 1634 1042139 N/A N/A 449783 449802 GGTTTTTTTCCCTTCTTTGG   8 1635 1042171 N/A N/A 450078 450097 GATTCTTCTTTAATCACTTC  31 1636 1042203 N/A N/A 450777 450796 CTCATCATCTTCTCAATTTC  86 1637 1042235 N/A N/A 451509 451528 CACAAACAACAATCATGTAC  47 1638 1042267 N/A N/A 451802 451821 CTACAAGCCCTTTATAACAG  26 1639 1042299 N/A N/A 452101 452120 TATTCTTGCCCAACACCAGG  80 1640 1042331 N/A N/A 452409 452428 GGTTTCAAAACTACATTTAC  58 1641 1042363 N/A N/A 452840 452859 TCTCAGGTACAAACTTTACA  26 1642 1042395 N/A N/A 453676 453695 TTCACCATCAACAGATCTGC  80 1643 1042427 N/A N/A 454375 454394 AGACAGTTTCAAGAAGGCCT 111 1644 1042459 N/A N/A 455186 455205 TCAGATCTTAAAAAAGGATG 102 1645 1042491 N/A N/A 456123 456142 AAGATAGTAAAAAGGCCAGG 135 1646 1042523 N/A N/A 456821 456840 ATCGAACCCCAGTAATGACA  38 1647

TABLE 23  Reduction of ATXN1 RNA by 5-10-5 MOE gapmers with mixed PO/PS linkages in A-431 Cells SEQ ID SEQ ID SEQ ID SEQ ID NO: 1 NO: 1 NO: 2 NO: 2 ATXN1 Compound Start Stop Start Stop (% SEQ Number Site Site Site Site Sequence (5′ to 3′) Control) ID NO  994605 N/A N/A  17726  17745 GTCACCTTTTCTATTTGCAC   3  138 1040092  1188  1207 435907 435926 TTGTGTAAACCTATTCCCTG  17 1648 1040124  2971  2990 457224 457243 ACACGGCAAATCAAAGAGCT  93 1649 1040156  3526  3545 457779 457798 AAGGTTAGAACAGAAACCTA  94 1650 1040188  4228  4247 458481 458500 CACCCCCAACCCCCCTTACC 112 1651 1040220  4721  4740 458974 458993 CCCTTTAAACCACATTGAAA  59 1652 1040252  5005  5024 459258 459277 CCCCAAACCTTTCCCACAAT  53 1653 1040284  5387  5406 459640 459659 ATGATATTTCGGATCTCTGG  11 1654 1040316  5699  5718 459952 459971 GTCAAGGAACTATTCTAGCT  22 1655 1040348  6113  6132 460366 460385 ATTCCTATACCTGAAATAGA  51 1656 1040380  6874  6893 461127 461146 CACCGAAGAATTTCTACCCC  54 1657 1040412  7385  7404 461638 461657 CTCACAATTCCAAGTTAGAA  23 1658 1040444  7827  7846 462080 462099 AGTAGTCACAGATGTTAAAG  16 1659 1040476  8211  8230 462464 462483 GATGTGTTCTTAAATTCTCT  14 1660 1040508  8526  8545 462779 462798 ACCTGTACTCCTCAAAGTGA  58 1661 1040540  8845  8864 463098 463117 AACAGTATTCTCAAATCGCA  73 1662 1040572  9267  9286 463520 463539 CTTAATATCCCCACAGCTGT 108 1663 1040604  9597  9616 463850 463869 TTGGCCATCCAGACAGCAAA  96 1664 1040636 10153 10172 464406 464425 TGCCCTCAACCCAAGTTCTG  82 1665 1040668 10376 10395 464629 464648 ATATGAATTCTTCCATTTTT  91 1666 1040700 N/A N/A   7886   7905 CGTTATAAAATATATTACTA  97 1667 1040732 N/A N/A  24555  24574 GCAAGATGAATTTATCCTCC  11 1668 1040764 N/A N/A  38983  39002 CACAACTTATTTTAATGTCA  13 1669 1040796 N/A N/A  66238  66257 TGAGTATTTTAAACTCTTCT 138 1670 1040828 N/A N/A  83133  83152 ATTCCATTATTTTAGAAAGC  50 1671 1040860 N/A N/A 105795 105814 ACTTGCAAAATTTCAAGTTT 131 1672 1040892 N/A N/A 138729 138748 AGCAAGTTAATTTATGGCCA 101 1673 1040924 N/A N/A 163155 163174 GATTGAATCATTTACCTCGC  49 1674 1040956 N/A N/A 185759 185778 ATCTGCTTTCTTTATTCCCT   9 1675 1040988 N/A N/A 207251 207270 ATCTCTGTTATTTAACACTG  70 1676 1041020 N/A N/A 224368 224387 TTCTTTAAAACTATTAGTCA 122 1677 1041052 N/A N/A 245320 245339 GACCTCAAAACCAAATTAGG 119 1678 1041084 N/A N/A 268039 268058 TCTGAAATTCAAAATCAGTG 122 1679 1041116 N/A N/A 284543 284562 CCACTGGAAATTTAACATGA  18 1680 1041148 N/A N/A 315438 315457 TGTATCACCCATTAACTGAC   2 1681 1041180 N/A N/A 332732 332751 GACTAAAAAATATACATCTC  57 1682 1041212 N/A N/A 356967 356986 GGTCTATTTCTTTACAGCAC   2 1683 1041244 N/A N/A 376250 376269 TTCTTCTGTATTTAATTCTT  18 1684 1041276 N/A N/A 407619 407638 ACTGAGTTTCAAAGCAAAGA  30 1685 1041308 N/A N/A 433762 433781 ATCCGATTTTAAAACAAACA  64 1686 1041340 N/A N/A 438045 438064 AGACATATTTTAAAACATGG  29 1687 1041372 N/A N/A 438476 438495 TAACCAATCCTAAACCCGTT  97 1688 1041404 N/A N/A 439022 439041 ATTAGCTAATTCCTAGAGGC  60 1689 1041436 N/A N/A 439388 439407 TGAATGTTTTCAAATCCTAG  31 1690 1041468 N/A N/A 440075 440094 CCATTTATTTTAAAAATCCT  69 1691 1041500 N/A N/A 440312 440331 CATTTCTAAACAAAACCTCT  95 1692 1041532 N/A N/A 440910 440929 CAGTAGAGAGATTTAGTGAT  15 1693 1041564 N/A N/A 441493 441512 TGGAGAAAACCATCTCTTCT 126 1694 1041596 N/A N/A 442101 442120 GTGAAGCATTAAAAAACGGA  28 1695 1041628 N/A N/A 442500 442519 CTGGCATTCCCCTTTCCTCC  92 1696 1041660 N/A N/A 442985 443004 TTGATTTATTTTTCAGCTGT  30 1697 1041692 N/A N/A 443241 443260 CCAATGCACCCCTCAAATCC 147 1698 1041724 N/A N/A 443784 443803 CCGATGACTCACAGCTCACA  46 1699 1041756 N/A N/A 444141 444160 GAGAGCATTTTTCTCCTTTT  25 1700 1041788 N/A N/A 444741 444760 GAACAACATAATATTCAGTG  10 1701 1041820 N/A N/A 445425 445444 TCATTAATAAAAACAGTCAA 102 1702 1041852 N/A N/A 445718 445737 TGACACTATCCCAGACATAC  34 1703 1041884 N/A N/A 445963 445982 CACCACTTAGTCAATAACTA  38 1704 1041916 N/A N/A 446261 446280 CCACCCTCCTCCACTCTTTC 138 1705 1041948 N/A N/A 446798 446817 GGGAGCAGTACCACAGATAA  34 1706 1041980 N/A N/A 447543 447562 GTGCTCAGTTAAAATCTGAA  29 1707 1042012 N/A N/A 448335 448354 CCCTCTAGTTTCCATAGCTT  60 1708 1042044 N/A N/A 448638 448657 CTTTTCCAAATACACCTAGA  46 1709 1042076 N/A N/A 448955 448974 TTGGTTAAGACCTAGTTTCT  52 1710 1042108 N/A N/A 449502 449521 TGGATGTGAAACAGAGACGG  17 1711 1042140 N/A N/A 449787 449806 ATAAGGTTTTTTTCCCTTCT  48 1712 1042172 N/A N/A 450079 450098 AGATTCTTCTTTAATCACTT  39 1713 1042204 N/A N/A 450800 450819 GAGATGGTACTTTAGAAGGC  14 1714 1042236 N/A N/A 451510 451529 ACACAAACAACAATCATGTA  56 1715 1042268 N/A N/A 451805 451824 TGTCTACAAGCCCTTTATAA  50 1716 1042300 N/A N/A 452105 452124 TGCTTATTCTTGCCCAACAC  35 1717 1042332 N/A N/A 452410 452429 TGGTTTCAAAACTACATTTA 105 1718 1042364 N/A N/A 452899 452918 GGCTATTTTTATAATGTGAA  25 1719 1042396 N/A N/A 453692 453711 ACAGTAATTAAAAGAATTCA  88 1720 1042428 N/A N/A 454436 454455 CAGAAGTTAATACTTGAGGA  71 1721 1042460 N/A N/A 455194 455213 GCAAAATATCAGATCTTAAA  65 1722 1042492 N/A N/A 456134 456153 GGACAGCAAATAAGATAGTA  48 1723 1042524 N/A N/A 456828 456847 CCAGTCAATCGAACCCCAGT  85 1724

TABLE 24  Reduction of ATXN1 RNA by 5-10-5 MOE gapmers with mixed PO/PS linkages in A-431 Cells SEQ ID SEQ ID SEQ ID SEQ ID NO: 1 NO: 1 NO: 2 NO: 2 ATXN1 Compound Start Stop Start Stop (% SEQ Number Site Site Site Site Sequence (5′ to 3′) Control) ID NO  994605 N/A N/A  17726  17745 GTCACCTTTTCTATTTGCAC   1  138 1040093  1189  1208 435908 435927 TTTGTGTAAACCTATTCCCT  23 1725 1040125  2998  3017 457251 457270 GCAGACATCCCCAACTGAGA  41 1726 1040157  3559  3578 457812 457831 CTCCTGCGACACACCTGCTG  58 1727 1040189  4287  4306 458540 458559 ATTGGTTTTCCTAACACTGC  54 1728 1040221  4722  4741 458975 458994 TCCCTTTAAACCACATTGAA  65 1729 1040253  5006  5025 459259 459278 CCCCCAAACCTTTCCCACAA  61 1730 1040285  5394  5413 459647 459666 CCCACAAATGATATTTCGGA  20 1731 1040317  5719  5738 459972 459991 GGTAATGAAATTCGAGGAAA  12 1732 1040349  6120  6139 460373 460392 TTTTATAATTCCTATACCTG  61 1733 1040381  6876  6895 461129 461148 GGCACCGAAGAATTTCTACC  28 1734 1040413  7386  7405 461639 461658 GCTCACAATTCCAAGTTAGA  17 1735 1040445  7830  7849 462083 462102 CTTAGTAGTCACAGATGTTA  27 1736 1040477  8225  8244 462478 462497 TATATTTATTACTTGATGTG  24 1737 1040509  8541  8560 462794 462813 ATTTTTTAAAACATTACCTG 112 1738 1040541  8869  8888 463122 463141 AGAAGTACTTTCAGCATAGG  12 1739 1040573  9268  9287 463521 463540 GCTTAATATCCCCACAGCTG 120 1740 1040605  9624  9643 463877 463896 TTGGCCACAGAAAAGGAGAC 110 1741 1040637 10159 10178 464412 464431 TGGTAGTGCCCTCAACCCAA  43 1742 1040669 10394 10413 464647 464666 CCACGATTAGAAAATAGAAT 108 1743 1040701 N/A N/A   8020   8039 TCAAACAAAATATAATGCTT  87 1744 1040733 N/A N/A  24636  24655 CTACACAAAACCAATCACTT  78 1745 1040765 N/A N/A  39292  39311 CGCCTTAATTTTTATTATAG  83 1746 1040797 N/A N/A  66579  66598 CCATTTAGAATATAGCTGTT  25 1747 1040829 N/A N/A  83570  83589 ATTCTCATCCATTATACTTT  48 1748 1040861 N/A N/A 106210 106229 TTACCAAAAACCATTTGTGT  21 1749 1040893 N/A N/A 138831 138850 TCCTTCTTTCAAAGTTCACC  26 1750 1040925 N/A N/A 163322 163341 CTGCCACTATTTTATGTCTG  59 1751 1040957 N/A N/A 185775 185794 CCCAGGTTCCCTTATCATCT  19 1752 1040989 N/A N/A 207430 207449 TTCTGCAAATAATTCCGTCA  23 1753 1041021 N/A N/A 224375 224394 CCATCATTTCTTTAAAACTA  67 1754 1041053 N/A N/A 246302 246321 AAGTACATACAAATACATAT 146 1755 1041085 N/A N/A 268505 268524 CCTATCAAAGCCACAACTTC 117 1756 1041117 N/A N/A 284846 284865 TTGTATACCATTTATGTTTC   2 1757 1041149 N/A N/A 315942 315961 CCACTCAAACCTTTCAATGC  20 1758 1041181 N/A N/A 334092 334111 GAGCTCAAACCCAAGTCTGT  72 1759 1041213 N/A N/A 357527 357546 ACCCTATTTCCTTAATGTAA  41 1760 1041245 N/A N/A 377993 378012 CTCCTTCACCCTTAAGGCTA  68 1761 1041277 N/A N/A 409360 409379 ATCGAGTCCTTTTAAACAAA  19 1762 1041309 N/A N/A 434288 434307 ACAACTCGCCATTAACACTA  65 1763 1041341 N/A N/A 438053 438072 AGCTAATAAGACATATTTTA 109 1764 1041373 N/A N/A 438477 438496 CTAACCAATCCTAAACCCGT 101 1765 1041405 N/A N/A 439023 439042 GATTAGCTAATTCCTAGAGG  42 1766 1041437 N/A N/A 439389 439408 TTGAATGTTTTCAAATCCTA  41 1767 1041469 N/A N/A 440076 440095 GCCATTTATTTTAAAAATCC  10 1768 1041501 N/A N/A 440313 440332 GCATTTCTAAACAAAACCTC  62 1769 1041533 N/A N/A 441017 441036 TGAGGAAGCCCTTCCCGGCA 115 1770 1041565 N/A N/A 441494 441513 TTGGAGAAAACCATCTCTTC 108 1771 1041597 N/A N/A 442114 442133 GGAAAGTATAAAAGTGAAGC  25 1772 1041629 N/A N/A 442524 442543 GCACGCAGTAACAATGGACA  31 1773 1041661 N/A N/A 442987 443006 CTTTGATTTATTTTTCAGCT  11 1774 1041693 N/A N/A 443288 443307 CCCTTGTTTCTGCATTGGTT  46 1775 1041725 N/A N/A 443792 443811 TGTTACCACCGATGACTCAC  42 1776 1041757 N/A N/A 444158 444177 GCACATACAGTTTAAAGGAG  12 1777 1041789 N/A N/A 444885 444904 GGTCCCTGTTCCTAGGGAGG 143 1778 1041821 N/A N/A 445439 445458 GCAATGTTTAAAAATCATTA  71 1779 1041853 N/A N/A 445722 445741 TTCATGACACTATCCCAGAC  46 1780 1041885 N/A N/A 445968 445987 CCTTTCACCACTTAGTCAAT  33 1781 1041917 N/A N/A 446266 446285 GCCTCCCACCCTCCTCCACT 101 1782 1041949 N/A N/A 446814 446833 ATGAAAATAAACTCATGGGA  84 1783 1041981 N/A N/A 447571 447590 GTCTAAAAGACTTCCTAGCA  78 1784 1042013 N/A N/A 448352 448371 TCTATTTAAAATAACAACCC 107 1785 1042045 N/A N/A 448641 448660 TTCCTTTTCCAAATACACCT  59 1786 1042077 N/A N/A 448969 448988 TAGAAGAGTATCTATTGGTT  32 1787 1042109 N/A N/A 449541 449560 CATCTCAAAACATGCTGTCA  86 1788 1042141 N/A N/A 449797 449816 GAGAAGTAAAATAAGGTTTT  62 1789 1042173 N/A N/A 450080 450099 GAGATTCTTCTTTAATCACT  27 1790 1042205 N/A N/A 451120 451139 GGAGATTTTACTTAATTTTT   8 1791 1042237 N/A N/A 451511 451530 TACACAAACAACAATCATGT  54 1792 1042269 N/A N/A 451817 451836 CTCATTAAGAAATGTCTACA  69 1793 1042301 N/A N/A 452128 452147 GACTCTCTACCAGAGTTGCG 102 1794 1042333 N/A N/A 452413 452432 ATTTGGTTTCAAAACTACAT  91 1795 1042365 N/A N/A 452900 452919 GGGCTATTTTTATAATGTGA  20 1796 1042397 N/A N/A 453702 453721 GTTCAGACAAACAGTAATTA  18 1797 1042429 N/A N/A 454481 454500 ACATAATTTGAATCCTAGGA 135 1798 1042461 N/A N/A 455196 455215 TAGCAAAATATCAGATCTTA  41 1799 1042493 N/A N/A 456136 456155 CTGGACAGCAAATAAGATAG  35 1800 1042525 N/A N/A 456836 456855 TGTTAGAACCAGTCAATCGA 116 1801

TABLE 25  Reduction of ATXN1 RNA by 5-10-5 MOE gapmers with mixed PO/PS linkages in A-431 Cells SEQ ID SEQ ID SEQ ID SEQ ID NO: 1 NO: 1 NO: 2 NO: 2 ATXN1 Compound Start Stop Start Stop (% SEQ Number Site Site Site Site Sequence (5′ to 3′) Control) ID NO  994605 N/A N/A  17726  17745 GTCACCTTTTCTATTTGCAC   2  138 1040094  1212  1231 435931 435950 TAGTCCAGCCCTGTGGACAA  47 1802 1040126  2999  3018 457252 457271 TGCAGACATCCCCAACTGAG  57 1803 1040158  3572  3591 457825 457844 CATATGCACCAGTCTCCTGC  65 1804 1040190  4299  4318 458552 458571 TGCAATAACCTGATTGGTTT  39 1805 1040222  4725  4744 458978 458997 TCATCCCTTTAAACCACATT  35 1806 1040254  5007  5026 459260 459279 TCCCCCAAACCTTTCCCACA  94 1807 1040286  5401  5420 459654 459673 TTCAAAACCCACAAATGATA  88 1808 1040318  5721  5740 459974 459993 AGGGTAATGAAATTCGAGGA  10 1809 1040350  6122  6141 460375 460394 TATTTTATAATTCCTATACC 108 1810 1040382  6919  6938 461172 461191 GGACATAGTACAGAGGCACA   8 1811 1040414  7387  7406 461640 461659 GGCTCACAATTCCAAGTTAG  32 1812 1040446  7840  7859 462093 462112 AATAGGTTTCCTTAGTAGTC  22 1813 1040478  8227  8246 462480 462499 TGTATATTTATTACTTGATG  10 1814 1040510  8546  8565 462799 462818 GTGCAATTTTTTAAAACATT  18 1815 1040542  8907  8926 463160 463179 GCAATGGCTTAAGAGTTTAG   9 1816 1040574  9269  9288 463522 463541 TGCTTAATATCCCCACAGCT  91 1817 1040606  9636  9655 463889 463908 AAGGCCTTCAGATTGGCCAC 125 1818 1040638 10161 10180 464414 464433 TCTGGTAGTGCCCTCAACCC  45 1819 1040670 10402 10421 464655 464674 TAGACACACCACGATTAGAA  68 1820 1040702 N/A N/A   8570   8589 ACTCAATATTTTTAAAACCC  28 1821 1040734 N/A N/A  25367  25386 GACTGAATTATTTATAGTTG  42 1822 1040766 N/A N/A  40104  40123 ATGCAATTTTAAATTCATGT  18 1823 1040798 N/A N/A  66787  66806 GGGAAAATTCCTTAGCATAT  30 1824 1040830 N/A N/A  83587  83606 GCTGAGTTCCAAAGCAAATT  35 1825 1040862 N/A N/A 106215 106234 ATGACTTACCAAAAACCATT 105 1826 1040894 N/A N/A 139215 139234 AGGGCTTAAATTTAACTGAA  28 1827 1040926 N/A N/A 163369 163388 AACGAAATTCCTTAAGGACA  62 1828 1040958 N/A N/A 185909 185928 TTGGTTCTATTTTATAATAG  66 1829 1040990 N/A N/A 207479 207498 AGACTACTATTTTATCACTG  19 1830 1041022 N/A N/A 225966 225985 TCACTTAAACCCAGGTCAGC  81 1831 1041054 N/A N/A 247054 247073 TTCCCCAAAATTTAGTTGTG  85 1832 1041086 N/A N/A 268668 268687 CTTCAACTATTTTATTTGGC  30 1833 1041118 N/A N/A 284950 284969 AGTAGAATTTAAAAGTAGAA 110 1834 1041150 N/A N/A 316219 316238 GGATTTCTAATTTAATCTTT  37 1835 1041182 N/A N/A 334729 334748 TAGTTCTTTCAAACTCCTTT   2 1836 1041214 N/A N/A 358497 358516 GCTATAATTCAAAATGCTCT 115 1837 1041246 N/A N/A 380363 380382 GCCTAAACAATTTATTCATT  31 1838 1041278 N/A N/A 409434 409453 ACCCTTCTATTTTATAAAGC  69 1839 1041310 N/A N/A 434517 434536 TGCAAGTTTCAAAAGAATTC 133 1840 1041342 N/A N/A 438074 438093 AAGGCATATACCACTGTACC  61 1841 1041374 N/A N/A 438478 438497 TCTAACCAATCCTAAACCCG 107 1842 1041406 N/A N/A 439043 439062 AGAGGTATAGTCTCTCCTAG  29 1843 1041438 N/A N/A 439430 439449 TGACTATTTTCAACTCAAGC  16 1844 1041470 N/A N/A 440085 440104 TATTATTATGCCATTTATTT  41 1845 1041502 N/A N/A 440315 440334 TCGCATTTCTAAACAAAACC  52 1846 1041534 N/A N/A 441019 441038 TTTGAGGAAGCCCTTCCCGG 119 1847 1041566 N/A N/A 441497 441516 GTTTTGGAGAAAACCATCTC  69 1848 1041598 N/A N/A 442146 442165 CTAATAAATTTTTACAAGGG  72 1849 1041630 N/A N/A 442542 442561 AAGGAGGCTTCCTTTGGTGC  70 1850 1041662 N/A N/A 442991 443010 AGGCCTTTGATTTATTTTTC 110 1851 1041694 N/A N/A 443385 443404 GATGGAAGCCAAAGGCTCCC 115 1852 1041726 N/A N/A 443794 443813 AATGTTACCACCGATGACTC  71 1853 1041758 N/A N/A 444206 444225 TCTGAGAGAATCAAAACATA  29 1854 1041790 N/A N/A 445090 445109 CTCACTTGCCTTCCTTTTCT  46 1855 1041822 N/A N/A 445440 445459 TGCAATGTTTAAAAATCATT  94 1856 1041854 N/A N/A 445730 445749 AACATTTTTTCATGACACTA  10 1857 1041886 N/A N/A 445969 445988 TCCTTTCACCACTTAGTCAA  47 1858 1041918 N/A N/A 446324 446343 TCTGTCTTTCATCTCTGGAT  44 1859 1041950 N/A N/A 446817 446836 CCAATGAAAATAAACTCATG  98 1860 1041982 N/A N/A 447576 447595 CCAGAGTCTAAAAGACTTCC 110 1861 1042014 N/A N/A 448353 448372 TTCTATTTAAAATAACAACC 116 1862 1042046 N/A N/A 448648 448667 GTATGGGTTCCTTTTCCAAA   7 1863 1042078 N/A N/A 449026 449045 AGTTTTAATAAAAGTTCAAC  96 1864 1042110 N/A N/A 449542 449561 CCATCTCAAAACATGCTGTC  78 1865 1042142 N/A N/A 449830 449849 ATGTACTTTTTCCCCCTTGG  65 1866 1042174 N/A N/A 450083 450102 TGGGAGATTCTTCTTTAATC  19 1867 1042206 N/A N/A 451121 451140 TGGAGATTTTACTTAATTTT  33 1868 1042238 N/A N/A 451518 451537 GATAATATACACAAACAACA  86 1869 1042270 N/A N/A 451821 451840 TAGACTCATTAAGAAATGTC  91 1870 1042302 N/A N/A 452129 452148 AGACTCTCTACCAGAGTTGC 100 1871 1042334 N/A N/A 452424 452443 TGTGTGACACTATTTGGTTT  74 1872 1042366 N/A N/A 452902 452921 CTGGGCTATTTTTATAATGT  30 1873 1042398 N/A N/A 453708 453727 AGACATGTTCAGACAAACAG  58 1874 1042430 N/A N/A 454483 454502 ACACATAATTTGAATCCTAG 110 1875 1042462 N/A N/A 455198 455217 ACTAGCAAAATATCAGATCT  49 1876 1042494 N/A N/A 456154 456173 ACTTTTTTTCTTATAGTACT  68 1877 1042526 N/A N/A 456838 456857 TCTGTTAGAACCAGTCAATC  51 1878

TABLE 26  Reduction of ATXN1 RNA by 5-10-5 MOE gapmers with mixed PO/PS linkages in A-431 Cells SEQ ID SEQ ID SEQ ID SEQ ID NO: 1 NO: 1 NO: 2 NO: 2 ATXN1 Compound Start Stop Start Stop (% SEQ Number Site Site Site Site Sequence (5′ to 3′) Control) ID NO  994605 N/A N/A  17726  17745 GTCACCTTTTCTATTTGCAC   2  138 1040095  1514  1533 436233 436252 TCAGACTGCCCATGTTGGCC  71 1879 1040127  3033  3052 457286 457305 GAGCCGTTCTTCAGGTTCTT  93 1880 1040159  3643  3662 457896 457915 GCCTGGAGCCCTGACCGCTC  60 1881 1040191  4300  4319 458553 458572 ATGCAATAACCTGATTGGTT  16 1882 1040223  4727  4746 458980 458999 ATTCATCCCTTTAAACCACA  15 1883 1040255  5011  5030 459264 459283 TCAGTCCCCCAAACCTTTCC  20 1884 1040287  5407  5426 459660 459679 GATGCATTCAAAACCCACAA  21 1885 1040319  5766  5785 460019 460038 TGACTGCAAGAATGAGCCCA  60 1886 1040351  6126  6145 460379 460398 CAATTATTTTATAATTCCTA  82 1887 1040383  6921  6940 461174 461193 GTGGACATAGTACAGAGGCA   7 1888 1040415  7388  7407 461641 461660 AGGCTCACAATTCCAAGTTA  26 1889 1040447  7865  7884 462118 462137 TGGAGATTTTTCTCTCTATG  36 1890 1040479  8228  8247 462481 462500 CTGTATATTTATTACTTGAT   7 1891 1040511  8566  8585 462819 462838 TCGACATTCATTTTTCTTTT  10 1892 1040543  8940  8959 463193 463212 ATGTCAAACATCATCTCTGA  12 1893 1040575  9272  9291 463525 463544 GGGTGCTTAATATCCCCACA 115 1894 1040607  9637  9656 463890 463909 GAAGGCCTTCAGATTGGCCA 101 1895 1040639 10163 10182 464416 464435 AGTCTGGTAGTGCCCTCAAC  17 1896 1040671 10407 10426 464660 464679 ACAAATAGACACACCACGAT  77 1897 1040703 N/A N/A   9147   9166 GTTGAGTTACAAATATAAAT  70 1898 1040735 N/A N/A  25394  25413 CCAGGATTTTAAAAAAAGCA  15 1899 1040767 N/A N/A  40413  40432 GCTAAATTTCCTTAAGCTTT  42 1900 1040799 N/A N/A  70441  70460 CATCAGTTCCAAAACCTGGA  83 1901 1040831 N/A N/A  83929  83948 CCAATACACCTTTATTTTTC  22 1902 1040863 N/A N/A 106559 106578 CGATTAATCCCTTATGTTTT   4 1903 1040895 N/A N/A 140193 140212 CTCTTCAAAAACATATCCGA  55 1904 1040927 N/A N/A 163438 163457 TTCTAAATTTAAAACTCCAA 101 1905 1040959 N/A N/A 186773 186792 ACAGGCAATATTTACTATAA   1 1906 1040991 N/A N/A 207544 207563 GCCTTCTTCCTTTATAGCAC  32 1907 1041023 N/A N/A 227246 227265 TTAGGCTATTAAATAATAGA 124 1908 1041055 N/A N/A 247203 247222 CTCAGTATCTTTTAATTGCC  29 1909 1041087 N/A N/A 269929 269948 TGGGCCAAAAACACCCCTTT  95 1910 1041119 N/A N/A 284975 284994 CTGTTTAAAAATGTATTGAG  23 1911 1041151 N/A N/A 316940 316959 GTCCCTTATCCTTAACACAC   2 1912 1041183 N/A N/A 334783 334802 CCCTAAATTTAAATTCTCTG  62 1913 1041215 N/A N/A 358611 358630 ACCTTTATTTAAATTTTCCA  22 1914 1041247 N/A N/A 380517 380536 GCTCAATATATTTATCTATT   1 1915 1041279 N/A N/A 410051 410070 TCTGTATTTTAAAAATCTCT  27 1916 1041311 N/A N/A 437693 437712 CGAGAACCCTTAATCCTGCC  34 1917 1041343 N/A N/A 438076 438095 CGAAGGCATATACCACTGTA  48 1918 1041375 N/A N/A 438482 438501 CCACTCTAACCAATCCTAAA  48 1919 1041407 N/A N/A 439087 439106 TTTTATTTTCTGATGCTTTG  10 1920 1041439 N/A N/A 439432 439451 CATGACTATTTTCAACTCAA   4 1921 1041471 N/A N/A 440089 440108 GCTGTATTATTATGCCATTT  12 1922 1041503 N/A N/A 440316 440335 GTCGCATTTCTAAACAAAAC  64 1923 1041535 N/A N/A 441116 441135 AGTGACAAATCATTGGTTGC  28 1924 1041567 N/A N/A 441513 441532 AGTCACAATGCCATCTGTTT  10 1925 1041599 N/A N/A 442147 442166 GCTAATAAATTTTTACAAGG  56 1926 1041631 N/A N/A 442566 442585 TGCTATCACCCTCCACTGAA  85 1927 1041663 N/A N/A 443017 443036 CTTCCATAAACTCTTTTTAG  45 1928 1041695 N/A N/A 443387 443406 CAGATGGAAGCCAAAGGCTC 117 1929 1041727 N/A N/A 443815 443834 CAGCTAATCCATTCAATGCA  60 1930 1041759 N/A N/A 444223 444242 GCTATAAACAACAACAGTCT  26 1931 1041791 N/A N/A 445120 445139 CACGGAAGCCCTTAGGCACA  63 1932 1041823 N/A N/A 445455 445474 GAGAGACCCATTTACTGCAA   8 1933 1041855 N/A N/A 445739 445758 GTTTTACAAAACATTTTTTC  56 1934 1041887 N/A N/A 445972 445991 AATTCCTTTCACCACTTAGT  16 1935 1041919 N/A N/A 446325 446344 CTCTGTCTTTCATCTCTGGA  49 1936 1041951 N/A N/A 446818 446837 CCCAATGAAAATAAACTCAT  77 1937 1041983 N/A N/A 447604 447623 CTCTTTCCCCAAACTCAGTG  30 1938 1042015 N/A N/A 448354 448373 GTTCTATTTAAAATAACAAC 109 1939 1042047 N/A N/A 448660 448679 TATAAGCAAACTGTATGGGT  13 1940 1042079 N/A N/A 449037 449056 TCAGGCTTTCCAGTTTTAAT  16 1941 1042111 N/A N/A 449544 449563 CTCCATCTCAAAACATGCTG  82 1942 1042143 N/A N/A 449832 449851 CAATGTACTTTTTCCCCCTT  32 1943 1042175 N/A N/A 450112 450131 AATGAAATTTATGTTAACCT  75 1944 1042207 N/A N/A 451122 451141 TTGGAGATTTTACTTAATTT  30 1945 1042239 N/A N/A 451523 451542 ACCGAGATAATATACACAAA   5 1946 1042271 N/A N/A 451863 451882 TAGGTAAACTTATCTGAGGA  15 1947 1042303 N/A N/A 452153 452172 TCAGGTGTTAACATCTGTCT  99 1948 1042335 N/A N/A 452453 452472 CTCATACAATTCTAGTTACC  45 1949 1042367 N/A N/A 452919 452938 GGGAAAGTTTCATTGTTCTG  24 1950 1042399 N/A N/A 453742 453761 GCAAAAAGATCCTTCCAGAA  62 1951 1042431 N/A N/A 454491 454510 GCTAACAGACACATAATTTG 111 1952 1042463 N/A N/A 455199 455218 CACTAGCAAAATATCAGATC  54 1953 1042495 N/A N/A 456155 456174 AACTTTTTTTCTTATAGTAC  66 1954 1042527 N/A N/A 456877 456896 TTCAAAATATTCCATCAAGT  25 1955

TABLE 27  Reduction of ATXN1 RNA by 5-10-5 MOE gapmers with mixed PO/PS linkages in A-431 Cells SEQ ID SEQ ID SEQ ID SEQ ID NO: 1 NO: 1 NO: 2 NO: 2 ATXN1 Compound Start Stop Start Stop (% SEQ Number Site Site Site Site Sequence (5′ to 3′) Control) ID NO  994605 N/A N/A  17726  17745 GTCACCTTTTCTATTTGCAC   1  138 1040096  1932  1951 436651 436670 TCACCGTTCAGGACCTCCTT  70 1956 1040128  3046  3065 457299 457318 GCCCTTTTTAACAGAGCCGT 122 1957 1040160  3669  3688 457922 457941 GCCCCGTTCCTTTCTTCCCC  67 1958 1040192  4313  4332 458566 458585 GGGAGTGAAGTCAATGCAAT  17 1959 1040224  4728  4747 458981 459000 CATTCATCCCTTTAAACCAC  22 1960 1040256  5013  5032 459266 459285 GTTCAGTCCCCCAAACCTTT  16 1961 1040288  5408  5427 459661 459680 AGATGCATTCAAAACCCACA  21 1962 1040320  5785  5804 460038 460057 CAGCACTAAATAAGCAGTAT  11 1963 1040352  6128  6147 460381 460400 ACCAATTATTTTATAATTCC  59 1964 1040384  6941  6960 461194 461213 CTGTCGGTAAATATTGCAAA  10 1965 1040416  7404  7423 461657 461676 CTAACAGAAAACATAGAGGC  28 1966 1040448  7866  7885 462119 462138 TTGGAGATTTTTCTCTCTAT  54 1967 1040480  8229  8248 462482 462501 TCTGTATATTTATTACTTGA  10 1968 1040512  8597  8616 462850 462869 GCCATATCTTTCAAACACTG   8 1969 1040544  8941  8960 463194 463213 AATGTCAAACATCATCTCTG  13 1970 1040576  9292  9311 463545 463564 AATTTAAGAATTGTAAGTGG 123 1971 1040608  9640  9659 463893 463912 AACGAAGGCCTTCAGATTGG 107 1972 1040640 10189 10208 464442 464461 TAGTTCTCCTCTGTACTGGC  14 1973 1040672 10409 10428 464662 464681 CTACAAATAGACACACCACG  70 1974 1040704 N/A N/A   9365   9384 AACAGTAGCCAAAATGTTCT 100 1975 1040736 N/A N/A  25410  25429 CTAGAATTTTAAAAAACCAG  80 1976 1040768 N/A N/A  40502  40521 AGTACAATCTTTTATAGATA  89 1977 1040800 N/A N/A  70463  70482 TGCCTGAGAATTTAATACTA  72 1978 1040832 N/A N/A  84147  84166 AGTAAGCTTCTTTAACTTTA  11 1979 1040864 N/A N/A 107690 107709 TGGATAATTATTTAATTCAT  70 1980 1040896 N/A N/A 140329 140348 CCAAACTAAGAATAATCTAG  89 1981 1040928 N/A N/A 165500 165519 GAGGAAATTATTTACTGGCT   5 1982 1040960 N/A N/A 187228 187247 ATGCACATACAAATAAGCTC  51 1983 1040992 N/A N/A 207564 207583 GAGATTAAAATACAATTGCT  36 1984 1041024 N/A N/A 227353 227372 GATTTCTCCTTTTAACCTCT  23 1985 1041056 N/A N/A 248796 248815 TTCTCAAAACCTTATCTCCT  92 1986 1041088 N/A N/A 270452 270471 CATTTTATTCCTTATCCTAC 118 1987 1041120 N/A N/A 285644 285663 CATTTGCACCTTTAATTTGT  24 1988 1041152 N/A N/A 316955 316974 TTCCAAAAAGAATGTGTCCC  16 1989 1041184 N/A N/A 335393 335412 GGTAGCTATCATTATTAAGC  19 1990 1041216 N/A N/A 358821 358840 CGACAGAAAATATATCTGCT  47 1991 1041248 N/A N/A 382312 382331 GACTGCAAAATTCCCATTGC  28 1992 1041280 N/A N/A 410115 410134 CTGTAAAAATACACATCCTC  38 1993 1041312 N/A N/A 437695 437714 CCCGAGAACCCTTAATCCTG  37 1994 1041344 N/A N/A 438160 438179 CACAGGTTCAGCCATAGCTC  21 1995 1041376 N/A N/A 438483 438502 TCCACTCTAACCAATCCTAA  66 1996 1041408 N/A N/A 439090 439109 CGCTTTTATTTTCTGATGCT  20 1997 1041440 N/A N/A 439433 439452 TCATGACTATTTTCAACTCA  18 1998 1041472 N/A N/A 440090 440109 AGCTGTATTATTATGCCATT  43 1999 1041504 N/A N/A 440317 440336 AGTCGCATTTCTAAACAAAA  66 2000 1041536 N/A N/A 441117 441136 AAGTGACAAATCATTGGTTG  21 2001 1041568 N/A N/A 441519 441538 GCCTAGAGTCACAATGCCAT  33 2002 1041600 N/A N/A 442148 442167 CGCTAATAAATTTTTACAAG  91 2003 1041632 N/A N/A 442620 442639 TCAACCAGAATCAAGGCATG  66 2004 1041664 N/A N/A 443022 443041 CTCTCCTTCCATAAACTCTT  69 2005 1041696 N/A N/A 443410 443429 GATGGGATAATATAGAACGC  45 2006 1041728 N/A N/A 443816 443835 CCAGCTAATCCATTCAATGC  34 2007 1041760 N/A N/A 444225 444244 ATGCTATAAACAACAACAGT  47 2008 1041792 N/A N/A 445122 445141 GACACGGAAGCCCTTAGGCA  46 2009 1041824 N/A N/A 445457 445476 GCGAGAGACCCATTTACTGC  11 2010 1041856 N/A N/A 445746 445765 GGCATCTGTTTTACAAAACA   9 2011 1041888 N/A N/A 445977 445996 AATAAAATTCCTTTCACCAC  35 2012 1041920 N/A N/A 446352 446371 CTTTATACTTTTGTAAGCTT  29 2013 1041952 N/A N/A 446819 446838 TCCCAATGAAAATAAACTCA 108 2014 1041984 N/A N/A 447606 447625 GCCTCTTTCCCCAAACTCAG  29 2015 1042016 N/A N/A 448356 448375 CAGTTCTATTTAAAATAACA 117 2016 1042048 N/A N/A 448668 448687 ATCCCAATTATAAGCAAACT  64 2017 1042080 N/A N/A 449039 449058 TTTCAGGCTTTCCAGTTTTA  20 2018 1042112 N/A N/A 449545 449564 TCTCCATCTCAAAACATGCT 108 2019 1042144 N/A N/A 449841 449860 CTACCTAGACAATGTACTTT  86 2020 1042176 N/A N/A 450127 450146 CCCACCTGGCCTGTTAATGA  86 2021 1042208 N/A N/A 451135 451154 CCAGCCTAAAAAATTGGAGA  94 2022 1042240 N/A N/A 451524 451543 CACCGAGATAATATACACAA  18 2023 1042272 N/A N/A 451875 451894 ACTGTGTTCTCATAGGTAAA  32 2024 1042304 N/A N/A 452173 452192 AAGTCATAAAAATAAAACTC  99 2025 1042336 N/A N/A 452454 452473 ACTCATACAATTCTAGTTAC  44 2026 1042368 N/A N/A 452952 452971 AGCATGAACCCCTTCTCCTG  78 2027 1042400 N/A N/A 453743 453762 AGCAAAAAGATCCTTCCAGA  90 2028 1042432 N/A N/A 454556 454575 ATAGAGACAAAAAGATGGTC 104 2029 1042464 N/A N/A 455200 455219 GCACTAGCAAAATATCAGAT  28 2030 1042496 N/A N/A 456172 456191 TCTGGACAAAATGTTTAAAC  35 2031 1042528 N/A N/A 456881 456900 AATATTCAAAATATTCCATC  64 2032

TABLE 28  Reduction of ATXN1 RNA by 5-10-5 MOE gapmers with mixed PO/PS linkages in A-431 Cells SEQ ID SEQ ID SEQ ID SEQ ID NO: 1 NO: 1 NO: 2 NO: 2 ATXN1 Compound Start Stop Start Stop (% SEQ Number Site Site Site Site Sequence (5′ to 3′) Control) ID NO  994605 N/A N/A  17726  17745 GTCACCTTTTCTATTTGCAC   2  138 1040097  1933  1952 436652 436671 CTCACCGTTCAGGACCTCCT  73 2033 1040129  3048  3067 457301 457320 TGGCCCTTTTTAACAGAGCC 113 2034 1040161  3670  3689 457923 457942 AGCCCCGTTCCTTTCTTCCC  46 2035 1040193  4328  4347 458581 458600 TTGCATCTACCTCTTGGGAG  44 2036 1040225  4729  4748 458982 459001 ACATTCATCCCTTTAAACCA  33 2037 1040257  5032  5051 459285 459304 GCTACATTTATTTATGCTCG  14 2038 1040289  5417  5436 459670 459689 GCACTTTAAAGATGCATTCA  29 2039 1040321  5786  5805 460039 460058 ACAGCACTAAATAAGCAGTA  28 2040 1040353  6129  6148 460382 460401 AACCAATTATTTTATAATTC 112 2041 1040385  6942  6961 461195 461214 GCTGTCGGTAAATATTGCAA  36 2042 1040417  7406  7425 461659 461678 ACCTAACAGAAAACATAGAG  36 2043 1040449  7882  7901 462135 462154 AGTGTCTTCAAAAGCATTGG  22 2044 1040481  8231  8250 462484 462503 TCTCTGTATATTTATTACTT  10 2045 1040513  8598  8617 462851 462870 AGCCATATCTTTCAAACACT   8 2046 1040545  8973  8992 463226 463245 TCTTTGGGTTTATAGGAACA  14 2047 1040577  9297  9316 463550 463569 TTCTGAATTTAAGAATTGTA  83 2048 1040609  9647  9666 463900 463919 CACTTCCAACGAAGGCCTTC 100 2049 1040641 10192 10211 464445 464464 CCCTAGTTCTCCTCTGTACT  79 2050 1040673 10414 10433 464667 464686 GTATCCTACAAATAGACACA  56 2051 1040705 N/A N/A   9443   9462 ACTCACTATTTTTAAGAGCA  49 2052 1040737 N/A N/A  25793  25812 CTGGGAATTTAAAAAACAAA  77 2053 1040769 N/A N/A  40905  40924 TCCATAAACATTTATACAGA   5 2054 1040801 N/A N/A  71139  71158 GGTTCAAAACCTTAGTCAGA  69 2055 1040833 N/A N/A  85391  85410 ATAGAATATTTTTATCATTC  91 2056 1040865 N/A N/A 108193 108212 GAATAAATTATTTACTGCGG   8 2057 1040897 N/A N/A 140551 140570 GGTCAATTTCAAACTGTTCT   5 2058 1040929 N/A N/A 166245 166264 GGCCTAAAACTATTCTTGAT 118 2059 1040961 N/A N/A 187483 187502 ACACTTAAACCTGTTAATAT  78 2060 1040993 N/A N/A 208043 208062 GCTCATAAAATACCTCTCTA  16 2061 1041025 N/A N/A 227432 227451 CCAGGAAAGATTTATTTAGC  51 2062 1041057 N/A N/A 250936 250955 AGCACATTTCAAAAGTTCAG  53 2063 1041089 N/A N/A 270476 270495 ATTCATTTTCCTTATGTTAC  58 2064 1041121 N/A N/A 286774 286793 TCACCCAAACCCATTGCCTA  77 2065 1041153 N/A N/A 317256 317275 TTCTGTAAAATATATCCTGT  19 2066 1041185 N/A N/A 335931 335950 ATCTGTAAAATATGGTTGCA   7 2067 1041217 N/A N/A 362937 362956 AACTTATTTTAAAGTGTCCA   2 2068 1041249 N/A N/A 385646 385665 ACATTATACCCTTAATATCC  39 2069 1041281 N/A N/A 410116 410135 GCTGTAAAAATACACATCCT  18 2070 1041313 N/A N/A 437751 437770 GCTTATTTTTTCTAGAGAAC  54 2071 1041345 N/A N/A 438169 438188 AGTGATAGTCACAGGTTCAG  12 2072 1041377 N/A N/A 438486 438505 TTATCCACTCTAACCAATCC 101 2073 1041409 N/A N/A 439093 439112 CCACGCTTTTATTTTCTGAT   1 2074 1041441 N/A N/A 439441 439460 CAGCTATTTCATGACTATTT   7 2075 1041473 N/A N/A 440091 440110 GAGCTGTATTATTATGCCAT 107 2076 1041505 N/A N/A 440318 440337 CAGTCGCATTTCTAAACAAA  76 2077 1041537 N/A N/A 441122 441141 CGGTAAAGTGACAAATCATT  12 2078 1041569 N/A N/A 441521 441540 CTGCCTAGAGTCACAATGCC  31 2079 1041601 N/A N/A 442149 442168 ACGCTAATAAATTTTTACAA 109 2080 1041633 N/A N/A 442624 442643 ACTCTCAACCAGAATCAAGG  86 2081 1041665 N/A N/A 443023 443042 CCTCTCCTTCCATAAACTCT  85 2082 1041697 N/A N/A 443457 443476 CTGTGTACTCTTCAGAGAAG  27 2083 1041729 N/A N/A 443817 443836 ACCAGCTAATCCATTCAATG  17 2084 1041761 N/A N/A 444251 444270 AACAATAGTCTTTAATTTTT 109 2085 1041793 N/A N/A 445143 445162 GTGAGTGACCACAGCAGCTG 110 2086 1041825 N/A N/A 445458 445477 AGCGAGAGACCCATTTACTG  23 2087 1041857 N/A N/A 445767 445786 CTGTTTTCACAAATTGCGAA  44 2088 1041889 N/A N/A 445978 445997 CAATAAAATTCCTTTCACCA  37 2089 1041921 N/A N/A 446354 446373 GCCTTTATACTTTTGTAAGC  73 2090 1041953 N/A N/A 446832 446851 GTTTCTGATTAAATCCCAAT  18 2091 1041985 N/A N/A 447607 447626 TGCCTCTTTCCCCAAACTCA  47 2092 1042017 N/A N/A 448370 448389 GAGAACTCCCCTGACAGTTC  90 2093 1042049 N/A N/A 448679 448698 ACATCACAAACATCCCAATT  71 2094 1042081 N/A N/A 449045 449064 GATACATTTCAGGCTTTCCA  13 2095 1042113 N/A N/A 449571 449590 CTTGAAATTCCCTTGGAGAG  42 2096 1042145 N/A N/A 449843 449862 AACTACCTAGACAATGTACT  65 2097 1042177 N/A N/A 450452 450471 CGTACTAAAACAAGATGACG  51 2098 1042209 N/A N/A 451136 451155 ACCAGCCTAAAAAATTGGAG  72 2099 1042241 N/A N/A 451525 451544 GCACCGAGATAATATACACA  13 2100 1042273 N/A N/A 451891 451910 TCTGAAAATAACATCTACTG  43 2101 1042305 N/A N/A 452175 452194 CCAAGTCATAAAAATAAAAC 104 2102 1042337 N/A N/A 452460 452479 ATAGCCACTCATACAATTCT  34 2103 1042369 N/A N/A 452953 452972 AAGCATGAACCCCTTCTCCT  66 2104 1042401 N/A N/A 453745 453764 GGAGCAAAAAGATCCTTCCA  91 2105 1042433 N/A N/A 454600 454619 GGATTCTCTAATTAGAGCTT  41 2106 1042465 N/A N/A 455224 455243 GAGGAGACCAGATAGCTTGT  79 2107 1042497 N/A N/A 456173 456192 CTCTGGACAAAATGTTTAAA  82 2108 1042529 N/A N/A 456883 456902 TCAATATTCAAAATATTCCA  98 2109

TABLE 29 Reduction of ATXN1 RNA by 5-10-5 MOE gapmers with mixed PO/PS linkages in A-431 Cells SEQ ID SEQ ID SEQ ID SEQ ID NO: 1 NO: 1 NO: 2 NO: 2 ATXN1 Compound Start Stop Start Stop (% SEQ Number Site Site Site Site Sequence (5′ to 3′) Control) ID NO 994605 N/A N/A 17726 17745 GTCACCTTTTCTATTTGCAC 3 138 1040098 2110 2129 436829 436848 GGGCAGGACCATCACAGAGG 60 2110 1040130 3049 3068 457302 457321 CTGGCCCTTTTTAACAGAGC 107 2111 1040162 3765 3784 458018 458037 CTGCAGGACCCTTCCCACGG 118 2112 1040194 4393 4412 458646 458665 TCAAAGACAAAAAGATTTCG 75 2113 1040226 4733 4752 458986 459005 ATTCACATTCATCCCTTTAA 35 2114 1040258 5048 5067 459301 459320 GTTAGAAAGAAATTTTGCTA 58 2115 1040290 5442 5461 459695 459714 CCTACTTATAAAACTTTTTT 114 2116 1040322 5787 5806 460040 460059 TACAGCACTAAATAAGCAGT 68 2117 1040354 6177 6196 460430 460449 CACATGCTAAAAAAGCAAGA 86 2118 1040386 6960 6979 461213 461232 AAGAAAGAACAAAAGACGGC 66 2119 1040418 7407 7426 461660 461679 CACCTAACAGAAAACATAGA 118 2120 1040450 7883 7902 462136 462155 TAGTGTCTTCAAAAGCATTG 39 2121 1040482 8238 8257 462491 462510 AGTATATTCTCTGTATATTT 29 2122 1040514 8599 8618 462852 462871 GAGCCATATCTTTCAAACAC 25 2123 1040546 8986 9005 463239 463258 TTCAAGATTATATTCTTTGG 52 2124 1040578 9328 9347 463581 463600 GTTGCCTTCAACGAGAAGGG 62 2125 1040610 9658 9677 463911 463930 ACTGTAAACAACACTTCCAA 22 2126 1040642 10204 10223 464457 464476 ACATCATTCCTTCCCTAGTT 29 2127 1040674 10415 10434 464668 464687 TGTATCCTACAAATAGACAC 78 2128 1040706 N/A N/A 9658 9677 GGCTGATTTTAAACTTAGTT 31 2129 1040738 N/A N/A 26160 26179 GTTTTATATTTTTAAGTGCT 7 2130 1040770 N/A N/A 40931 40950 ACATTTAAAATATTTCAGAC 108 2131 1040802 N/A N/A 71486 71505 TGTCTATTTTAAAGACTCAA 112 2132 1040834 N/A N/A 85731 85750 GGATATCTATTTTAATTCTT 62 2133 1040866 N/A N/A 108791 108810 ACAGTATTTCAAAAGAAGCC 73 2134 1040898 N/A N/A 140712 140731 CTGGATAATACCTAACTGTC 58 2135 1040930 N/A N/A 167395 167414 AGTGACTTAGATTATCCTTT 17 2136 1040962 N/A N/A 187991 188010 CACATCAAACCTCAAGGGCA 64 2137 1040994 N/A N/A 208238 208257 GTTTCCCTAATTTATGGAGT 52 2138 1041026 N/A N/A 227529 227548 ATTCTTACAATTTACTTGTA 96 2139 1041058 N/A N/A 251431 251450 ATTCTCTTTTAAAGATAAAG 119 2140 1041090 N/A N/A 270489 270508 CTATGGTTTTAAAATTCATT 82 2141 1041122 N/A N/A 287171 287190 ACTACCAGCCCTTATTTCAG 20 2142 1041154 N/A N/A 318500 318519 CTCTGCTTTCAAATGTGTTT 6 2143 1041186 N/A N/A 338862 338881 TCTTTCATATTTTAAAGTGC 3 2144 1041218 N/A N/A 365191 365210 TCCAGTAAAAACACAACACT 44 2145 1041250 N/A N/A 385654 385673 TATAATATACATTATACCCT 78 2146 1041282 N/A N/A 410286 410305 CCACAATTACAAACACACTT 41 2147 1041314 N/A N/A 437752 437771 GGCTTATTTTTTCTAGAGAA 18 2148 1041346 N/A N/A 438171 438190 GCAGTGATAGTCACAGGTTC 19 2149 1041378 N/A N/A 438490 438509 GGAATTATCCACTCTAACCA 56 2150 1041410 N/A N/A 439101 439120 TGTATTAACCACGCTTTTAT 31 2151 1041442 N/A N/A 439443 439462 AGCAGCTATTTCATGACTAT 19 2152 1041474 N/A N/A 440093 440112 GTGAGCTGTATTATTATGCC 62 2153 1041506 N/A N/A 440327 440346 GCAAGGAACCAGTCGCATTT 56 2154 1041538 N/A N/A 441144 441163 AGCCGATTTCTGATAGGCTC 78 2155 1041570 N/A N/A 441530 441549 GCAGGATTTCTGCCTAGAGT 39 2156 1041602 N/A N/A 442188 442207 ATGTTCATCTTAATGCTCTT 21 2157 1041634 N/A N/A 442625 442644 GACTCTCAACCAGAATCAAG 111 2158 1041666 N/A N/A 443025 443044 TGCCTCTCCTTCCATAAACT 89 2159 1041698 N/A N/A 443481 443500 TTTTACAACTCCACTGAGCA 53 2160 1041730 N/A N/A 443834 443853 CTCGGCTATTTTTAGGTACC 51 2161 1041762 N/A N/A 444258 444277 TGCTTTAAACAATAGTCTTT 81 2162 1041794 N/A N/A 445146 445165 CCAGTGAGTGACCACAGCAG 99 2163 1041826 N/A N/A 445484 445503 ACCCCGTCTCAAAGATGAAG 102 2164 1041858 N/A N/A 445769 445788 CCCTGTTTTCACAAATTGCG 62 2165 1041890 N/A N/A 445979 445998 TCAATAAAATTCCTTTCACC 60 2166 1041922 N/A N/A 446355 446374 GGCCTTTATACTTTTGTAAG 103 2167 1041954 N/A N/A 446834 446853 TGGTTTCTGATTAAATCCCA 49 2168 1041986 N/A N/A 447630 447649 TTTACTTGTATATTTGTCTG 15 2169 1042018 N/A N/A 448384 448403 CTGTCCTTTTCAGAGAGAAC 88 2170 1042050 N/A N/A 448680 448699 TACATCACAAACATCCCAAT 97 2171 1042082 N/A N/A 449048 449067 AATGATACATTTCAGGCTTT 47 2172 1042114 N/A N/A 449591 449610 ATATATCATCAAATCTGTTG 44 2173 1042146 N/A N/A 449851 449870 TTAGTGTGAACTACCTAGAC 85 2174 1042178 N/A N/A 450505 450524 CTGCCGAAAAATTCACGAGA 95 2175 1042210 N/A N/A 451137 451156 AACCAGCCTAAAAAATTGGA 88 2176 1042242 N/A N/A 451539 451558 AGGATAATTTTATGGCACCG 14 2177 1042274 N/A N/A 451905 451924 GCAATATTTAATTTTCTGAA 36 2178 1042306 N/A N/A 452185 452204 TGCTGCAAATCCAAGTCATA 51 2179 1042338 N/A N/A 452464 452483 CCTTATAGCCACTCATACAA 42 2180 1042370 N/A N/A 452976 452995 AGTACATTCATATGGCAGCT 27 2181 1042402 N/A N/A 453759 453778 GGCGAATTCTATATGGAGCA 98 2182 1042434 N/A N/A 454604 454623 AACTGGATTCTCTAATTAGA 59 2183 1042466 N/A N/A 455257 455276 GCATTCAATTTAAAAAAGGG 66 2184 1042498 N/A N/A 456187 456206 AATAAATTTAAAAACTCTGG 108 2185 1042530 N/A N/A 456884 456903 ATCAATATTCAAAATATTCC 89 2186

TABLE 30 Reduction of ATXN1 RNA by 5-10-5 MOE gapmers with mixed PO/PS linkages in A-431 Cells SEQ ID SEQ ID SEQ ID SEQ ID NO: 1 NO: 1 NO: 2 NO: 2 ATXN1 Compound Start Stop Start Stop (% SEQ Number Site Site Site Site Sequence (5′ to 3′) Control) ID NO 994605 N/A N/A 17726 17745 GTCACCTTTTCTATTTGCAC 2 138 1040099 2149 2168 436868 436887 CTGTTGCACCTCCAGGTCAG 77 2187 1040131 3050 3069 457303 457322 GCTGGCCCTTTTTAACAGAG 110 2188 1040163 3800 3819 458053 458072 CCTGTGCACCCCCACATGCG 107 2189 1040195 4416 4435 458669 458688 TGAACTATAAACAGTACTAG 69 2190 1040227 4734 4753 458987 459006 AATTCACATTCATCCCTTTA 34 2191 1040259 5079 5098 459332 459351 AACCTTATAAAATGGCCTAG 70 2192 1040291 5446 5465 459699 459718 TCTCCCTACTTATAAAACTT 31 2193 1040323 5788 5807 460041 460060 ATACAGCACTAAATAAGCAG 77 2194 1040355 6207 6226 460460 460479 GGTCAGACTCTATTGGCACA 10 2195 1040387 6987 7006 461240 461259 TTACTAGTTTAAAAATGGAA 100 2196 1040419 7414 7433 461667 461686 ACACACTCACCTAACAGAAA 68 2197 1040451 7915 7934 462168 462187 CTTCCTCACCCATATCTGAA 45 2198 1040483 8250 8269 462503 462522 GCTTTATAAAAAAGTATATT 139 2199 1040515 8600 8619 462853 462872 AGAGCCATATCTTTCAAACA 31 2200 1040547 8988 9007 463241 463260 TGTTCAAGATTATATTCTTT 73 2201 1040579 9332 9351 463585 463604 AACAGTTGCCTTCAACGAGA 29 2202 1040611 9661 9680 463914 463933 ATTACTGTAAACAACACTTC 52 2203 1040643 10205 10224 464458 464477 AACATCATTCCTTCCCTAGT 33 2204 1040675 10418 10437 464671 464690 GAGTGTATCCTACAAATAGA 53 2205 1040707 N/A N/A 11372 11391 TCTAGCAAACCTCTTTTTCC 57 2206 1040739 N/A N/A 27282 27301 AGGTATAAATCCCCTTTCCA 31 2207 1040771 N/A N/A 41291 41310 GATAGTAATCAAACCTGAGT 43 2208 1040803 N/A N/A 71489 71508 ATTTGTCTATTTTAAAGACT 117 2209 1040835 N/A N/A 87443 87462 ATGAGTAAAATATGGTCCTT 43 2210 1040867 N/A N/A 109082 109101 CACTTCATAATTTAATATTT 92 2211 1040899 N/A N/A 141267 141286 GTGATATTTTAAAGACTTAC 6 2212 1040931 N/A N/A 168114 168133 AGGGCCTTATTTTAATCACA 106 2213 1040963 N/A N/A 188513 188532 CATTTATTTCCTTACCCAGT 6 2214 1040995 N/A N/A 208356 208375 GTGTCTAAAACCAACTGGGT 28 2215 1041027 N/A N/A 227703 227722 AAGCCAATATTTTATTTTGA 96 2216 1041059 N/A N/A 251853 251872 GGTGATAAAGATATCATTAC 67 2217 1041091 N/A N/A 270781 270800 TTCGAAATTCTTTATTTGAT 136 2218 1041123 N/A N/A 287520 287539 CACTATAAAGAATGATGAGT 5 2219 1041155 N/A N/A 318566 318585 TAGAGAAAACGATGTTGGCT 3 2220 1041187 N/A N/A 339528 339547 CCTTCGGCTATTTAATAATA 75 2221 1041219 N/A N/A 365605 365624 AGGCATCTAATTTAAATTCA 20 2222 1041251 N/A N/A 386171 386190 GCTTGTAAAACTATGGCGGC 87 2223 1041283 N/A N/A 413867 413886 GGCAATAAAATATTTAATGG 71 2224 1041315 N/A N/A 437753 437772 GGGCTTATTTTTTCTAGAGA 33 2225 1041347 N/A N/A 438223 438242 ACATTATATATATGTTGGAG 16 2226 1041379 N/A N/A 438493 438512 ACTGGAATTATCCACTCTAA 40 2227 1041411 N/A N/A 439103 439122 ATTGTATTAACCACGCTTTT 29 2228 1041443 N/A N/A 439444 439463 TAGCAGCTATTTCATGACTA 15 2229 1041475 N/A N/A 440117 440136 GTGAACAGCCACTACAGAGG 76 2230 1041507 N/A N/A 440360 440379 CCTTCATTCTCAAGCTGAAG 88 2231 1041539 N/A N/A 441150 441169 GATGTCAGCCGATTTCTGAT 30 2232 1041571 N/A N/A 441554 441573 AGGCATCCTCAAGAGTCTGT 32 2233 1041603 N/A N/A 442192 442211 GTACATGTTCATCTTAATGC 12 2234 1041635 N/A N/A 442626 442645 GGACTCTCAACCAGAATCAA 118 2235 1041667 N/A N/A 443027 443046 GCTGCCTCTCCTTCCATAAA 64 2236 1041699 N/A N/A 443488 443507 CAATACATTTTACAACTCCA 27 2237 1041731 N/A N/A 443871 443890 CTGACTCTACAGGCTCATGT 51 2238 1041763 N/A N/A 444259 444278 CTGCTTTAAACAATAGTCTT 70 2239 1041795 N/A N/A 445170 445189 AGGGATGGCCAGGAAGGACA 96 2240 1041827 N/A N/A 445492 445511 ATCAGAAAACCCCGTCTCAA 104 2241 1041859 N/A N/A 445770 445789 TCCCTGTTTTCACAAATTGC 68 2242 1041891 N/A N/A 445980 445999 TTCAATAAAATTCCTTTCAC 93 2243 1041923 N/A N/A 446357 446376 ATGGCCTTTATACTTTTGTA 116 2244 1041955 N/A N/A 446849 446868 ACACATTTTCCAGAATGGTT 16 2245 1041987 N/A N/A 447638 447657 CTTTTTTATTTACTTGTATA 80 2246 1042019 N/A N/A 448386 448405 CACTGTCCTTTTCAGAGAGA 68 2247 1042051 N/A N/A 448682 448701 CTTACATCACAAACATCCCA 95 2248 1042083 N/A N/A 449050 449069 CTAATGATACATTTCAGGCT 46 2249 1042115 N/A N/A 449593 449612 ATATATATCATCAAATCTGT 23 2250 1042147 N/A N/A 449862 449881 CTCCTCACTAATTAGTGTGA 110 2251 1042179 N/A N/A 450507 450526 GCCTGCCGAAAAATTCACGA 144 2252 1042211 N/A N/A 451139 451158 CCAACCAGCCTAAAAAATTG 122 2253 1042243 N/A N/A 451540 451559 TAGGATAATTTTATGGCACC 8 2254 1042275 N/A N/A 451908 451927 CAGGCAATATTTAATTTTCT 11 2255 1042307 N/A N/A 452186 452205 TTGCTGCAAATCCAAGTCAT 34 2256 1042339 N/A N/A 452466 452485 TGCCTTATAGCCACTCATAC 33 2257 1042371 N/A N/A 452978 452997 TGAGTACATTCATATGGCAG 13 2258 1042403 N/A N/A 453760 453779 TGGCGAATTCTATATGGAGC 63 2259 1042435 N/A N/A 454638 454657 AGTTGAATAGACATGGATTA 73 2260 1042467 N/A N/A 455281 455300 ACTTTCACAATTTTGCAAAT 45 2261 1042499 N/A N/A 456211 456230 TCTGAACAAAAATATAAGCA 106 2262 1042531 N/A N/A 456890 456909 AAGGTCATCAATATTCAAAA 19 2263

TABLE 31 Reduction of ATXN1 RNA by 5-10-5 MOE gapmers with mixed PO/PS linkages in A-431 Cells SEQ ID SEQ ID SEQ ID SEQ ID NO: 1 NO: 1 NO: 2 NO: 2 ATXN1 Compound Start Stop Start Stop (% SEQ Number Site Site Site Site Sequence (5′ to 3′) Control) ID NO 994605 N/A N/A 17726 17745 GTCACCTTTTCTATTTGCAC 3 138 1040100 2215 2234 436934 436953 AGGCTTCCCTAAATGCAGGC 69 2264 1040132 3098 3117 457351 457370 GGCCGTCGGCCTTTGAGTGC 106 2265 1040164 3838 3857 458091 458110 AGGCAGAGAAAAAGAGACCC 72 2266 1040196 4421 4440 458674 458693 AGTCATGAACTATAAACAGT 34 2267 1040228 4736 4755 458989 459008 ATAATTCACATTCATCCCTT 28 2268 1040260 5084 5103 459337 459356 AACATAACCTTATAAAATGG 82 2269 1040292 5447 5466 459700 459719 TTCTCCCTACTTATAAAACT 48 2270 1040324 5798 5817 460051 460070 CGTTTAAAAAATACAGCACT 49 2271 1040356 6228 6247 460481 460500 GCTTTAACTATATAGCACAC 78 2272 1040388 6995 7014 461248 461267 GCCTGCTGTTACTAGTTTAA 31 2273 1040420 7415 7434 461668 461687 AACACACTCACCTAACAGAA 47 2274 1040452 7920 7939 462173 462192 CTCTGCTTCCTCACCCATAT 36 2275 1040484 8251 8270 462504 462523 TGCTTTATAAAAAAGTATAT 128 2276 1040516 8606 8625 462859 462878 TTCAACAGAGCCATATCTTT 65 2277 1040548 8989 9008 463242 463261 GTGTTCAAGATTATATTCTT 40 2278 1040580 9344 9363 463597 463616 GTTAGCTACCAGAACAGTTG 40 2279 1040612 9667 9686 463920 463939 GTAAGGATTACTGTAAACAA 12 2280 1040644 10208 10227 464461 464480 CAAAACATCATTCCTTCCCT 84 2281 1040676 10419 10438 464672 464691 CGAGTGTATCCTACAAATAG 56 2282 1040708 N/A N/A 11914 11933 TGCCAGAGAATTTATATGTA 10 2283 1040740 N/A N/A 27352 27371 CCTGTCAAAACCAGTCACTC 60 2284 1040772 N/A N/A 41515 41534 CTAATAATAGTCTAATTACA 134 2285 1040804 N/A N/A 71673 71692 TTGTGCTTTTAAATTCAAAC 10 2286 1040836 N/A N/A 87528 87547 ACATCCTTTTAAATGTTAGG 31 2287 1040868 N/A N/A 109301 109320 TGTCTTAATCAAACCTCCCG 50 2288 1040900 N/A N/A 141437 141456 CAGTTCTATTTTTAGTTATA 10 2289 1040932 N/A N/A 168436 168455 ATTTACCTTCTTTAACACAA 66 2290 1040964 N/A N/A 188787 188806 GGGATATTTTAAAATTCTAC 54 2291 1040996 N/A N/A 208934 208953 CCTGGGTTTCAAAGATTCCT 100 2292 1041028 N/A N/A 229640 229659 TAGAGAATTCAAAGCACCAA 46 2293 1041060 N/A N/A 253001 253020 TCAAAGTTTTAAAGAGTTTT 88 2294 1041092 N/A N/A 271090 271109 TGCTCCAAACCCAGCTCCTC 132 2295 1041124 N/A N/A 288911 288930 CCCTACTCCTTTTATAGATG 32 2296 1041156 N/A N/A 319014 319033 TCATCCAAACCCAGACGGGT 120 2297 1041188 N/A N/A 339984 340003 ATAAAGTCCTTTTAACCCCT 4 2298 1041220 N/A N/A 367208 367227 GTGCCCTTTTAAAATCTTTT 6 2299 1041252 N/A N/A 386698 386717 AGCCAAAAATACATCCACCT 24 2300 1041284 N/A N/A 413882 413901 ACTGTAATCTAAACAGGCAA 87 2301 1041316 N/A N/A 437786 437805 TTCATTACACACAGCAGAGA 26 2302 1041348 N/A N/A 438225 438244 AGACATTATATATATGTTGG 27 2303 1041380 N/A N/A 438512 438531 CCCCTACACCCCAGAGCACA 109 2304 1041412 N/A N/A 439104 439123 GATTGTATTAACCACGCTTT 18 2305 1041444 N/A N/A 439457 439476 TGAATGTCCCAAATAGCAGC 34 2306 1041476 N/A N/A 440138 440157 CACCCCTAATTCATGCAGGA 72 2307 1041508 N/A N/A 440361 440380 GCCTTCATTCTCAAGCTGAA 43 2308 1041540 N/A N/A 441162 441181 TTTAGCTGTGATGATGTCAG 51 2309 1041572 N/A N/A 441556 441575 TCAGGCATCCTCAAGAGTCT 68 2310 1041604 N/A N/A 442235 442254 CTTTAGTTCCCATGAGGTCT 41 2311 1041636 N/A N/A 442680 442699 AAGTGGATTATATTTGGCAG 7 2312 1041668 N/A N/A 443031 443050 ATCAGCTGCCTCTCCTTCCA 47 2313 1041700 N/A N/A 443489 443508 CCAATACATTTTACAACTCC 57 2314 1041732 N/A N/A 443874 443893 GGACTGACTCTACAGGCTCA 41 2315 1041764 N/A N/A 444260 444279 ACTGCTTTAAACAATAGTCT 65 2316 1041796 N/A N/A 445235 445254 TTTTTCTTACACATGGTAGC 28 2317 1041828 N/A N/A 445506 445525 TCAGCATGAAAAAAATCAGA 76 2318 1041860 N/A N/A 445772 445791 AGTCCCTGTTTTCACAAATT 45 2319 1041892 N/A N/A 446016 446035 GCTTTTAAGAAAAATTTTAG 123 2320 1041924 N/A N/A 446359 446378 GGATGGCCTTTATACTTTTG 52 2321 1041956 N/A N/A 446875 446894 TCATTTTATGATCTTGCTGG 25 2322 1041988 N/A N/A 447659 447678 CTGGTTATCTTCTTATGCAT 89 2323 1042020 N/A N/A 448422 448441 TTTGGAATCTTTTTTGCCTC 44 2324 1042052 N/A N/A 448684 448703 CTCTTACATCACAAACATCC 102 2325 1042084 N/A N/A 449054 449073 GTTCCTAATGATACATTTCA 52 2326 1042116 N/A N/A 449594 449613 AATATATATCATCAAATCTG 46 2327 1042148 N/A N/A 449866 449885 TTTTCTCCTCACTAATTAGT 112 2328 1042180 N/A N/A 450508 450527 AGCCTGCCGAAAAATTCACG 116 2329 1042212 N/A N/A 451152 451171 CCATAAAAACCCTCCAACCA 112 2330 1042244 N/A N/A 451541 451560 CTAGGATAATTTTATGGCAC 9 2331 1042276 N/A N/A 451909 451928 GCAGGCAATATTTAATTTTC 37 2332 1042308 N/A N/A 452218 452237 GGAAACCAATCCCACATCAA 78 2333 1042340 N/A N/A 452472 452491 AGTGTTTGCCTTATAGCCAC 20 2334 1042372 N/A N/A 452979 452998 TTGAGTACATTCATATGGCA 30 2335 1042404 N/A N/A 453783 453802 TGCTAAAGAAAAAGAATTGT 111 2336 1042436 N/A N/A 454643 454662 TTTCCAGTTGAATAGACATG 62 2337 1042468 N/A N/A 455285 455304 AATTACTTTCACAATTTTGC 27 2338 1042500 N/A N/A 456212 456231 CTCTGAACAAAAATATAAGC 87 2339 1042532 N/A N/A 456957 456976 ACACACTATAAATGAGGCTC 46 2340

TABLE 32 Reduction of ATXN1 RNA by 5-10-5 MOE gapmers with mixed PO/PS linkages in A-431 Cells SEQ ID SEQ ID SEQ ID SEQ ID NO: 1 NO: 1 NO: 2 NO: 2 ATXN1 Compound Start Stop Start Stop (% SEQ Number Site Site Site Site Sequence (5′ to 3′) Control) ID NO 994605 N/A N/A 17726 17745 GTCACCTTTTCTATTTGCAC 3 138 1040101 2216 2235 436935 436954 CAGGCTTCCCTAAATGCAGG 70 2341 1040133 3109 3128 457362 457381 GCTGCCCGCCAGGCCGTCGG 111 2342 1040165 3880 3899 458133 458152 CCCCCCCGGCCCATGCCGAT 108 2343 1040197 4422 4441 458675 458694 TAGTCATGAACTATAAACAG 46 2344 1040229 4738 4757 458991 459010 TCATAATTCACATTCATCCC 16 2345 1040261 5106 5125 459359 459378 GACCAAAATGAATTTTCAAA 26 2346 1040293 5458 5477 459711 459730 TATTTAAAAATTTCTCCCTA 95 2347 1040325 5902 5921 460155 460174 TCTTACCATCAAAGGCTAAA 60 2348 1040357 6229 6248 460482 460501 AGCTTTAACTATATAGCACA 107 2349 1040389 7040 7059 461293 461312 CCTGACTAATTTCTTGGTGA 46 2350 1040421 7422 7441 461675 461694 AAAACCCAACACACTCACCT 116 2351 1040453 7964 7983 462217 462236 GACAACCAACACAGCTCAAG 83 2352 1040485 8252 8271 462505 462524 GTGCTTTATAAAAAAGTATA 94 2353 1040517 8613 8632 462866 462885 TCATTGTTTCAACAGAGCCA 12 2354 1040549 8990 9009 463243 463262 CGTGTTCAAGATTATATTCT 49 2355 1040581 9345 9364 463598 463617 AGTTAGCTACCAGAACAGTT 52 2356 1040613 9711 9730 463964 463983 TGTCACCTAATACTTGGTAT 25 2357 1040645 10211 10230 464464 464483 GTGCAAAACATCATTCCTTC 10 2358 1040677 10436 10455 464689 464708 AATTCAATAAACAGACTCGA 40 2359 1040709 N/A N/A 12342 12361 TTCAGAATTTAAAATTCAGC 15 2360 1040741 N/A N/A 27434 27453 ACAATTAGCCAAAACTGAAT 45 2361 1040773 N/A N/A 42923 42942 CGTTCCAAATTATTCCTGCT 7 2362 1040805 N/A N/A 72788 72807 ATTTGCTCCTTTTATCATTG 7 2363 1040837 N/A N/A 87598 87617 ACATTATTTCAAAACCCACA 49 2364 1040869 N/A N/A 110925 110944 TAGTGGTTAGATTAACAGCT 6 2365 1040901 N/A N/A 141588 141607 GTCTCATAACGATAACCAAA 23 2366 1040933 N/A N/A 169799 169818 ACCTTTAAAATTTTTTCAGC 94 2367 1040965 N/A N/A 189270 189289 GCTTACAAAGCCATAGAACC 67 2368 1040997 N/A N/A 209089 209108 GTCTACAGCCTTTAACGACT 85 2369 1041029 N/A N/A 229753 229772 CCAGTTAACCAAAAAATTTT 119 2370 1041061 N/A N/A 255397 255416 GGCTACTATCAAATACATTT 9 2371 1041093 N/A N/A 271117 271136 TGTTTATTTCAAACTTTCCC 55 2372 1041125 N/A N/A 289433 289452 GGTCTTGGCCCTTAACTGTT 20 2373 1041157 N/A N/A 319225 319244 CCCTGATAAATTTATGAATT 50 2374 1041189 N/A N/A 341174 341193 TTTGATCTGCCTTATCTCTG 14 2375 1041221 N/A N/A 367501 367520 TTTGTATTTTAAACTGAGTG 5 2376 1041253 N/A N/A 386699 386718 AAGCCAAAAATACATCCACC 46 2377 1041285 N/A N/A 414009 414028 CTTTTTAGAATACCATGCCC 95 2378 1041317 N/A N/A 437788 437807 AATTCATTACACACAGCAGA 8 2379 1041349 N/A N/A 438226 438245 AAGACATTATATATATGTTG 89 2380 1041381 N/A N/A 438520 438539 AAGGACAGCCCCTACACCCC 97 2381 1041413 N/A N/A 439106 439125 CAGATTGTATTAACCACGCT 5 2382 1041445 N/A N/A 439471 439490 TGTTTTATTTTATCTGAATG 61 2383 1041477 N/A N/A 440139 440158 CCACCCCTAATTCATGCAGG 67 2384 1041509 N/A N/A 440364 440383 GCTGCCTTCATTCTCAAGCT 81 2385 1041541 N/A N/A 441172 441191 GGTGGAGTATTTTAGCTGTG 10 2386 1041573 N/A N/A 441564 441583 TTATGAGTTCAGGCATCCTC 15 2387 1041605 N/A N/A 442237 442256 GGCTTTAGTTCCCATGAGGT 20 2388 1041637 N/A N/A 442682 442701 TTAAGTGGATTATATTTGGC 11 2389 1041669 N/A N/A 443041 443060 CTAGACTTTCATCAGCTGCC 53 2390 1041701 N/A N/A 443490 443509 ACCAATACATTTTACAACTC 34 2391 1041733 N/A N/A 443877 443896 AAGGGACTGACTCTACAGGC 16 2392 1041765 N/A N/A 444289 444308 GACCTCTCTCTACTTGCTGT 30 2393 1041797 N/A N/A 445239 445258 TGGGTTTTTCTTACACATGG 9 2394 1041829 N/A N/A 445574 445593 GTCTTGTTTTACCTGTAGAG 6 2395 1041861 N/A N/A 445787 445806 CATTTCCTTCACAAGAGTCC 78 2396 1041893 N/A N/A 446036 446055 CCTAATCTGACTAATGACTG 94 2397 1041925 N/A N/A 446361 446380 AGGGATGGCCTTTATACTTT 46 2398 1041957 N/A N/A 446885 446904 AATCATTAAGTCATTTTATG 79 2399 1041989 N/A N/A 447660 447679 ACTGGTTATCTTCTTATGCA 120 2400 1042021 N/A N/A 448436 448455 ACTCTCTCCATTCATTTGGA 52 2401 1042053 N/A N/A 448685 448704 TCTCTTACATCACAAACATC 94 2402 1042085 N/A N/A 449059 449078 TGAGGGTTCCTAATGATACA 41 2403 1042117 N/A N/A 449599 449618 GTGAGAATATATATCATCAA 100 2404 1042149 N/A N/A 449885 449904 CTTGCCAGCCCAATGCTAGT 95 2405 1042181 N/A N/A 450520 450539 CATAGCTAGAACAGCCTGCC 107 2406 1042213 N/A N/A 451153 451172 CCCATAAAAACCCTCCAACC 102 2407 1042245 N/A N/A 451542 451561 GCTAGGATAATTTTATGGCA 40 2408 1042277 N/A N/A 451926 451945 TATACACACTTCACAGGGCA 56 2409 1042309 N/A N/A 452223 452242 CAGAAGGAAACCAATCCCAC 80 2410 1042341 N/A N/A 452473 452492 CAGTGTTTGCCTTATAGCCA 11 2411 1042373 N/A N/A 452982 453001 AACTTGAGTACATTCATATG 72 2412 1042405 N/A N/A 453799 453818 TGGAATATCTTTACAGTGCT 38 2413 1042437 N/A N/A 454668 454687 CACTGAAATCAAGAATGCAA 81 2414 1042469 N/A N/A 455287 455306 TGAATTACTTTCACAATTTT 73 2415 1042501 N/A N/A 456214 456233 AACTCTGAACAAAAATATAA 151 2416 1042533 N/A N/A 456961 456980 AGCCACACACTATAAATGAG 99 2417

TABLE 33 Reduction of ATXN1 RNA by 5-10-5 MOE gapmers with mixed PO/PS linkages in A-431 Cells SEQ ID SEQ ID SEQ ID SEQ ID NO: 1 NO: 1 NO: 2 NO: 2 ATXN1 Compound Start Stop Start Stop (% SEQ Number Site Site Site Site Sequence (5′ to 3′) Control) ID NO 994605 N/A N/A 17726 17745 GTCACCTTTTCTATTTGCAC 3 138 1040102 2217 2236 436936 436955 CCAGGCTTCCCTAAATGCAG 92 2418 1040134 3141 3160 457394 457413 ATTCCGTTTTCCTGCTCGGC 32 2419 1040166 3890 3909 458143 458162 CTGCTCTGAACCCCCCCGGC 100 2420 1040198 4429 4448 458682 458701 TTGTCCATAGTCATGAACTA 78 2421 1040230 4739 4758 458992 459011 TTCATAATTCACATTCATCC 10 2422 1040262 5119 5138 459372 459391 GATGTGGTAAAAAGACCAAA 38 2423 1040294 5459 5478 459712 459731 ATATTTAAAAATTTCTCCCT 90 2424 1040326 5904 5923 460157 460176 CCTCTTACCATCAAAGGCTA 57 2425 1040358 6230 6249 460483 460502 GAGCTTTAACTATATAGCAC 44 2426 1040390 7045 7064 461298 461317 TTCGCCCTGACTAATTTCTT 25 2427 1040422 7450 7469 461703 461722 GGATGCTGCCACTTCCTGGT 66 2428 1040454 7968 7987 462221 462240 CCATGACAACCAACACAGCT 131 2429 1040486 8278 8297 462531 462550 CCAACCCAACACAATAGCAG 33 2430 1040518 8615 8634 462868 462887 ACTCATTGTTTCAACAGAGC 27 2431 1040550 9008 9027 463261 463280 CCCTTGTTACAAACACTTCG 65 2432 1040582 9369 9388 463622 463641 CCCTCCCGCCATTACACAGG 83 2433 1040614 9714 9733 463967 463986 TAGTGTCACCTAATACTTGG 59 2434 1040646 10212 10231 464465 464484 GGTGCAAAACATCATTCCTT 21 2435 1040678 10442 10461 464695 464714 CCATAAAATTCAATAAACAG 108 2436 1040710 N/A N/A 13427 13446 ATAAGCTTTCTTTAAATGCA 9 2437 1040742 N/A N/A 27656 27675 GTGTTCTTTCTTTAACAGTT 4 2438 1040774 N/A N/A 42927 42946 CCCCCGTTCCAAATTATTCC 106 2439 1040806 N/A N/A 74008 74027 GTTTTTATCCATTACAAGAG 22 2440 1040838 N/A N/A 88730 88749 ACCCGCAATCAAATACTGCC 73 2441 1040870 N/A N/A 111213 111232 CTAATGTGCCCTTAACATGG 95 2442 1040902 N/A N/A 141663 141682 GCTCATAAAACCATGTGCTC 100 2443 1040934 N/A N/A 170327 170346 GCTTGATTTTAAACTTTATA 40 2444 1040966 N/A N/A 190544 190563 ACCCTCAAACGAATAGGCTC 145 2445 1040998 N/A N/A 209796 209815 TCCACACAAGAATAATCTAC 86 2446 1041030 N/A N/A 230401 230420 GCTAGGAAAATTTACCATAC 29 2447 1041062 N/A N/A 255626 255645 GATTAAATAATTTAAGCACA 110 2448 1041094 N/A N/A 271334 271353 TCTTGGGTTCCTTATATTAC 56 2449 1041126 N/A N/A 290352 290371 TAGGTGTTTATTTAGAACCC 12 2450 1041158 N/A N/A 319445 319464 TCATGCTTTCAAAACACAGT 11 2451 1041190 N/A N/A 342628 342647 AATGAAATCATTTACTGAAC 85 2452 1041222 N/A N/A 368463 368482 AGTGTAATACATTACTCATA 5 2453 1041254 N/A N/A 387051 387070 GTATACAAAGATATAACCTG 76 2454 1041286 N/A N/A 418439 418458 TGTTTGTTTTAAAATTAGGG 72 2455 1041318 N/A N/A 437792 437811 GGTTAATTCATTACACACAG 3 2456 1041350 N/A N/A 438237 438256 ACCTAAATAATAAGACATTA 141 2457 1041382 N/A N/A 438532 438551 AGCCAGACAACTAAGGACAG 80 2458 1041414 N/A N/A 439107 439126 TCAGATTGTATTAACCACGC 5 2459 1041446 N/A N/A 439472 439491 TTGTTTTATTTTATCTGAAT 95 2460 1041478 N/A N/A 440143 440162 GTACCCACCCCTAATTCATG 119 2461 1041510 N/A N/A 440366 440385 TGGCTGCCTTCATTCTCAAG 106 2462 1041542 N/A N/A 441188 441207 TGTGGCAAACACAGCTGGTG 45 2463 1041574 N/A N/A 441611 441630 ATACTATATCACACTGCTTT 58 2464 1041606 N/A N/A 442251 442270 GTTTTATATGCCATGGCTTT 58 2465 1041638 N/A N/A 442691 442710 TGGAGGATATTAAGTGGATT 22 2466 1041670 N/A N/A 443042 443061 TCTAGACTTTCATCAGCTGC 66 2467 1041702 N/A N/A 443492 443511 TTACCAATACATTTTACAAC 72 2468 1041734 N/A N/A 443917 443936 GGCATGTTCAATGTTGGCAA 16 2469 1041766 N/A N/A 444314 444333 ACAGGGAAAACTGTTAGGTG 7 2470 1041798 N/A N/A 445240 445259 CTGGGTTTTTCTTACACATG 10 2471 1041830 N/A N/A 445576 445595 CAGTCTTGTTTTACCTGTAG 6 2472 1041862 N/A N/A 445791 445810 CTCCCATTTCCTTCACAAGA 53 2473 1041894 N/A N/A 446044 446063 GTCACCTTCCTAATCTGACT 106 2474 1041926 N/A N/A 446679 446698 CCTTTATAACTTTTCTTTCT 28 2475 1041958 N/A N/A 446891 446910 GTTAGTAATCATTAAGTCAT 5 2476 1041990 N/A N/A 447677 447696 CCCTGGTGCCAAAAGGGACT 100 2477 1042022 N/A N/A 448475 448494 TCTTTAACCCCTCTTGCGCC 123 2478 1042054 N/A N/A 448687 448706 TTTCTCTTACATCACAAACA 116 2479 1042086 N/A N/A 449060 449079 TTGAGGGTTCCTAATGATAC 54 2480 1042118 N/A N/A 449600 449619 AGTGAGAATATATATCATCA 122 2481 1042150 N/A N/A 449916 449935 AATCTGATCATTGTAGGCAC 12 2482 1042182 N/A N/A 450530 450549 TGGTGTGAACCATAGCTAGA 120 2483 1042214 N/A N/A 451161 451180 ACCCCCCTCCCATAAAAACC 117 2484 1042246 N/A N/A 451566 451585 GGTTTTACCCTTTCCTGCAC 90 2485 1042278 N/A N/A 451931 451950 CACATTATACACACTTCACA 78 2486 1042310 N/A N/A 452244 452263 TCATTAACAACATAAACTGA 74 2487 1042342 N/A N/A 452495 452514 CATGGTACAGATAATTGTGA 57 2488 1042374 N/A N/A 453018 453037 TACTGGATCCATACAAGGCA 33 2489 1042406 N/A N/A 453800 453819 ATGGAATATCTTTACAGTGC 17 2490 1042438 N/A N/A 454669 454688 CCACTGAAATCAAGAATGCA 121 2491 1042470 N/A N/A 455290 455309 TCTTGAATTACTTTCACAAT 24 2492 1042502 N/A N/A 456227 456246 GAGGACAACTAAAAACTCTG 105 2493 1042534 N/A N/A 456962 456981 CAGCCACACACTATAAATGA 112 2494

TABLE 34 Reduction of ATXN1 RNA by 5-10-5 MOE gapmers with mixed PO/PS linkages in A-431 Cells SEQ ID SEQ ID SEQ ID SEQ ID NO: 1 NO: 1 NO: 2 NO: 2 ATXN1 Compound Start Stop Start Stop (% SEQ Number Site Site Site Site Sequence (5′ to 3′) Control) ID NO 994605 N/A N/A 17726 17745 GTCACCTTTTCTATTTGCAC 2 138 1040103 2218 2237 436937 436956 GCCAGGCTTCCCTAAATGCA 135 2495 1040135 3180 3199 457433 457452 TCGCCATTCTCAGAGAGCAT 79 2496 1040167 3909 3928 458162 458181 TGGGAACCCCAGGAGGACAC 54 2497 1040199 4484 4503 458737 458756 ATCTAATTCCTCATGTCACA 15 2498 1040231 4740 4759 458993 459012 GTTCATAATTCACATTCATC 8 2499 1040263 5161 5180 459414 459433 CAGAGTTTCTAAGAGCCCGC 38 2500 1040295 5460 5479 459713 459732 AATATTTAAAAATTTCTCCC 110 2501 1040327 5906 5925 460159 460178 TTCCTCTTACCATCAAAGGC 38 2502 1040359 6232 6251 460485 460504 ATGAGCTTTAACTATATAGC 31 2503 1040391 7049 7068 461302 461321 TCTTTTCGCCCTGACTAATT 32 2504 1040423 7495 7514 461748 461767 AAGAGGTGTGAAAGGTTCCG 27 2505 1040455 7969 7988 462222 462241 GCCATGACAACCAACACAGC 96 2506 1040487 8283 8302 462536 462555 GGAAACCAACCCAACACAAT 73 2507 1040519 8662 8681 462915 462934 ACTTTCAACCCTTCTCTGCT 53 2508 1040551 9010 9029 463263 463282 ATCCCTTGTTACAAACACTT 33 2509 1040583 9370 9389 463623 463642 TCCCTCCCGCCATTACACAG 94 2510 1040615 9719 9738 463972 463991 TGAGCTAGTGTCACCTAATA 12 2511 1040647 10213 10232 464466 464485 AGGTGCAAAACATCATTCCT 36 2512 1040679 10447 10466 464700 464719 AGGGACCATAAAATTCAATA 22 2513 1040711 N/A N/A 14141 14160 CTCCTCCAAATTTATCTTCA 56 2514 1040743 N/A N/A 28302 28321 CACAAAATACATTAAGTCCT 27 2515 1040775 N/A N/A 43117 43136 TCCAGCAAAATATTTCTTTA 39 2516 1040807 N/A N/A 74082 74101 TTGATCAACCAAAGATGGCT 39 2517 1040839 N/A N/A 88777 88796 CCAATGGCTTTTTAACAGAT 27 2518 1040871 N/A N/A 112988 113007 AACACATTAGATTATGAGTA 11 2519 1040903 N/A N/A 141741 141760 AGGGTGTTATTTTAGAGTAA 13 2520 1040935 N/A N/A 171157 171176 GCTGGAAAAGAATCTGAGCA 114 2521 1040967 N/A N/A 190616 190635 GTTATATTATTTTATCCCTT 14 2522 1040999 N/A N/A 209931 209950 GAAGATATCTTTTATGACAC 23 2523 1041031 N/A N/A 231711 231730 CACAGTAGCCAAAAGCAGTC 95 2524 1041063 N/A N/A 255652 255671 GTATATATTATTTAAAATGT 101 2525 1041095 N/A N/A 273041 273060 AGCTGGTTTCTTTAGCCACC 81 2526 1041127 N/A N/A 290740 290759 GACTGAAAAATACCCAGCCA 102 2527 1041159 N/A N/A 322660 322679 TAGGCCTTATTTTATTCCAT 72 2528 1041191 N/A N/A 342814 342833 TGAGCTTTTTAAAAACAGTT 4 2529 1041223 N/A N/A 369251 369270 TTTCTTAGCCAAAGAGATAT 85 2530 1041255 N/A N/A 387144 387163 TGTTCAATTTAAAAGCCTTG 5 2531 1041287 N/A N/A 418795 418814 ATCTGCAAAGAATCTGCCCC 72 2532 1041319 N/A N/A 437793 437812 AGGTTAATTCATTACACACA 5 2533 1041351 N/A N/A 438241 438260 TCATACCTAAATAATAAGAC 102 2534 1041383 N/A N/A 438533 438552 CAGCCAGACAACTAAGGACA 57 2535 1041415 N/A N/A 439116 439135 CCTGACTTCTCAGATTGTAT 50 2536 1041447 N/A N/A 439505 439524 ATTCAAACCATTAATTAGTT 73 2537 1041479 N/A N/A 440144 440163 AGTACCCACCCCTAATTCAT 98 2538 1041511 N/A N/A 440368 440387 AGTGGCTGCCTTCATTCTCA 52 2539 1041543 N/A N/A 441206 441225 GACTCTGAACCTGTCACTTG 83 2540 1041575 N/A N/A 441613 441632 CCATACTATATCACACTGCT 21 2541 1041607 N/A N/A 442255 442274 CTCAGTTTTATATGCCATGG 44 2542 1041639 N/A N/A 442692 442711 TTGGAGGATATTAAGTGGAT 14 2543 1041671 N/A N/A 443043 443062 TTCTAGACTTTCATCAGCTG 102 2544 1041703 N/A N/A 443494 443513 CTTTACCAATACATTTTACA 61 2545 1041735 N/A N/A 443936 443955 ATTCATCGCCACCAAGCTCG 48 2546 1041767 N/A N/A 444343 444362 ATCTATCACACCAATGCAAG 29 2547 1041799 N/A N/A 445241 445260 GCTGGGTTTTTCTTACACAT 25 2548 1041831 N/A N/A 445587 445606 AGTGAAATTCTCAGTCTTGT 37 2549 1041863 N/A N/A 445806 445825 GTTGTTTAAATATGTCTCCC 8 2550 1041895 N/A N/A 446045 446064 TGTCACCTTCCTAATCTGAC 51 2551 1041927 N/A N/A 446680 446699 GCCTTTATAACTTTTCTTTC 11 2552 1041959 N/A N/A 446892 446911 TGTTAGTAATCATTAAGTCA 12 2553 1041991 N/A N/A 447705 447724 CCAAAAAATCTTCTTCCATG 45 2554 1042023 N/A N/A 448476 448495 TTCTTTAACCCCTCTTGCGC 94 2555 1042055 N/A N/A 448712 448731 CTTGGAATCATACTTTCTTC 55 2556 1042087 N/A N/A 449061 449080 ATTGAGGGTTCCTAATGATA 46 2557 1042119 N/A N/A 449602 449621 TCAGTGAGAATATATATCAT 98 2558 1042151 N/A N/A 449921 449940 CAGATAATCTGATCATTGTA 45 2559 1042183 N/A N/A 450531 450550 GTGGTGTGAACCATAGCTAG 97 2560 1042215 N/A N/A 451169 451188 CCCCCCATACCCCCCTCCCA 92 2561 1042247 N/A N/A 451567 451586 GGGTTTTACCCTTTCCTGCA 99 2562 1042279 N/A N/A 451933 451952 GCCACATTATACACACTTCA 13 2563 1042311 N/A N/A 452245 452264 GTCATTAACAACATAAACTG 21 2564 1042343 N/A N/A 452496 452515 CCATGGTACAGATAATTGTG 105 2565 1042375 N/A N/A 453045 453064 CTGATACATTTCTAGAATGA 28 2566 1042407 N/A N/A 453852 453871 TCACAGTTTACATCTCAACA 28 2567 1042439 N/A N/A 454686 454705 TAGAATTAAAATATACACCA 69 2568 1042471 N/A N/A 455291 455310 GTCTTGAATTACTTTCACAA 9 2569 1042503 N/A N/A 456245 456264 TGGACCAACCCTCCTTCTGA 81 2570 1042535 N/A N/A 456967 456986 TCCCCCAGCCACACACTATA 102 2571

TABLE 35 Reduction of ATXN1 RNA by 5-10-5 MOE gapmers with mixed PO/PS linkages in A-431 Cells SEQ ID SEQ ID SEQ ID SEQ ID NO: 1 NO: 1 NO: 2 NO: 2 ATXN1 Compound Start Stop Start Stop (% SEQ Number Site Site Site Site Sequence (5′ to 3′) Control) ID NO 994605 N/A N/A 17726 17745 GTCACCTTTTCTATTTGCAC 1 138 1040104 2348 2367 437067 437086 TCAGGTAGCCGATGACAGGG 44 2572 1040136 3181 3200 457434 457453 TTCGCCATTCTCAGAGAGCA 57 2573 1040168 3937 3956 458190 458209 GCTGGGTTCCTGATGTTGAT 31 2574 1040200 4485 4504 458738 458757 AATCTAATTCCTCATGTCAC 21 2575 1040232 4741 4760 458994 459013 AGTTCATAATTCACATTCAT 13 2576 1040264 5162 5181 459415 459434 TCAGAGTTTCTAAGAGCCCG 17 2577 1040296 5477 5496 459730 459749 GCAGCCATCCAAGTAAGAAT 16 2578 1040328 5913 5932 460166 460185 GCCCGTATTCCTCTTACCAT 12 2579 1040360 6268 6287 460521 460540 GGAAGATCAACCAAACAAGG 46 2580 1040392 7061 7080 461314 461333 GTATTATTTTTTTCTTTTCG 11 2581 1040424 7563 7582 461816 461835 CAGAGCAGTCAAAGTGCTGC 118 2582 1040456 7970 7989 462223 462242 AGCCATGACAACCAACACAG 63 2583 1040488 8289 8308 462542 462561 AAGAGAGGAAACCAACCCAA 50 2584 1040520 8663 8682 462916 462935 AACTTTCAACCCTTCTCTGC 37 2585 1040552 9040 9059 463293 463312 ATAATGAGTCCTGTTTGATT 20 2586 1040584 9377 9396 463630 463649 CCGGTGTTCCCTCCCGCCAT 85 2587 1040616 9772 9791 464025 464044 CAGAGAAAACCTGTGCACCG 71 2588 1040648 10214 10233 464467 464486 AAGGTGCAAAACATCATTCC 35 2589 1040680 10463 10482 464716 464735 AAGCACCATCAAAGAAAGGG 24 2590 1040712 N/A N/A 14174 14193 ACCCAATTTCAAAGATCACT 29 2591 1040744 N/A N/A 28305 28324 GTTCACAAAATACATTAAGT 6 2592 1040776 N/A N/A 43918 43937 AGATCAATTCAAAGGCTCCT 62 2593 1040808 N/A N/A 74369 74388 GATTTGTATTTTTAATTGAC 58 2594 1040840 N/A N/A 89862 89881 TTGACATTTTAAAACAGCTC 40 2595 1040872 N/A N/A 114285 114304 AAGCTTATCCAAAAACATTT 70 2596 1040904 N/A N/A 143859 143878 CCCCTCAACCAAACTTTTAC 116 2597 1040936 N/A N/A 172540 172559 TATTAATTTCATTACCATGA 92 2598 1040968 N/A N/A 190768 190787 CCTAGAATACATTATTCCTC 56 2599 1041000 N/A N/A 209947 209966 AGCATATTTTAAAGAAGAAG 76 2600 1041032 N/A N/A 233011 233030 GTCCATACACCTTAATAAGT 29 2601 1041064 N/A N/A 256096 256115 GATTACTTTTAAAAGCAACA 54 2602 1041096 N/A N/A 273624 273643 CCTAAAAGAATTTATCCATA 96 2603 1041128 N/A N/A 290841 290860 CTTGGCAAATTATTATCTGC 12 2604 1041160 N/A N/A 322672 322691 GCTAAGAAAATATAGGCCTT 73 2605 1041192 N/A N/A 343258 343277 GGCTTTATAGTCTAAGTTGC 7 2606 1041224 N/A N/A 369453 369472 ACTTCAAACCTTTATCAGTT 3 2607 1041256 N/A N/A 388260 388279 CAAACCCAAATTTAGCTCTG 41 2608 1041288 N/A N/A 420471 420490 CCTTTAAGCCCTTAAAGCTG 110 2609 1041320 N/A N/A 437794 437813 GAGGTTAATTCATTACACAC 5 2610 1041352 N/A N/A 438248 438267 GGCCTTATCATACCTAAATA 61 2611 1041384 N/A N/A 438538 438557 ACCAGCAGCCAGACAACTAA 66 2612 1041416 N/A N/A 439148 439167 TACCCCAAGCCCAGCAGGTC 108 2613 1041448 N/A N/A 439513 439532 CCAAAACAATTCAAACCATT 40 2614 1041480 N/A N/A 440152 440171 TTTCTCCTAGTACCCACCCC 78 2615 1041512 N/A N/A 440369 440388 AAGTGGCTGCCTTCATTCTC 44 2616 1041544 N/A N/A 441287 441306 GGAACCTCAATTAAGTCCAG 38 2617 1041576 N/A N/A 441615 441634 CACCATACTATATCACACTG 29 2618 1041608 N/A N/A 442256 442275 CCTCAGTTTTATATGCCATG 6 2619 1041640 N/A N/A 442706 442725 TTATGGCCTCAAACTTGGAG 53 2620 1041672 N/A N/A 443046 443065 TCTTTCTAGACTTTCATCAG 33 2621 1041704 N/A N/A 443496 443515 CACTTTACCAATACATTTTA 80 2622 1041736 N/A N/A 443941 443960 TTAGGATTCATCGCCACCAA 19 2623 1041768 N/A N/A 444346 444365 CCAATCTATCACACCAATGC 24 2624 1041800 N/A N/A 445254 445273 TCCCACATTAAAAGCTGGGT 109 2625 1041832 N/A N/A 445593 445612 TCTGCAAGTGAAATTCTCAG 66 2626 1041864 N/A N/A 445849 445868 GTACATATCACCAAAAACAA 57 2627 1041896 N/A N/A 446046 446065 ATGTCACCTTCCTAATCTGA 26 2628 1041928 N/A N/A 446684 446703 AATAGCCTTTATAACTTTTC 18 2629 1041960 N/A N/A 446894 446913 TGTGTTAGTAATCATTAAGT 19 2630 1041992 N/A N/A 447708 447727 CTGCCAAAAAATCTTCTTCC 50 2631 1042024 N/A N/A 448482 448501 TGCTGGTTCTTTAACCCCTC 40 2632 1042056 N/A N/A 448729 448748 GCTGTTCAATCAAGCACCTT 76 2633 1042088 N/A N/A 449072 449091 CTCAAAATATTATTGAGGGT 35 2634 1042120 N/A N/A 449604 449623 TCTCAGTGAGAATATATATC 103 2635 1042152 N/A N/A 449922 449941 TCAGATAATCTGATCATTGT 54 2636 1042184 N/A N/A 450547 450566 CTTAGAATTAAATGCTGTGG 63 2637 1042216 N/A N/A 451173 451192 GTCTCCCCCCATACCCCCCT 81 2638 1042248 N/A N/A 451670 451689 AACTCCAAAGACACCACTCT 86 2639 1042280 N/A N/A 451934 451953 AGCCACATTATACACACTTC 16 2640 1042312 N/A N/A 452252 452271 TCTTAGAGTCATTAACAACA 15 2641 1042344 N/A N/A 452506 452525 TGGGCTTGTTCCATGGTACA 42 2642 1042376 N/A N/A 453046 453065 TCTGATACATTTCTAGAATG 36 2643 1042408 N/A N/A 453854 453873 ACTCACAGTTTACATCTCAA 16 2644 1042440 N/A N/A 454687 454706 GTAGAATTAAAATATACACC 17 2645 1042472 N/A N/A 455293 455312 AGGTCTTGAATTACTTTCAC 7 2646 1042504 N/A N/A 456246 456265 TTGGACCAACCCTCCTTCTG 114 2647 1042536 N/A N/A 456983 457002 TTTGCAAACCTCCCTCTCCC 106 2648

TABLE 36 Reduction of ATXN1 RNA by 5-10-5 MOE gapmers with mixed PO/PS linkages in A-431 Cells SEQ ID SEQ ID SEQ ID SEQ ID NO: 1 NO: 1 NO: 2 NO: 2 ATXN1 Compound Start Stop Start Stop (% SEQ Number Site Site Site Site Sequence (5′ to 3′) Control) ID NO 994605 N/A N/A 17726 17745 GTCACCTTTTCTATTTGCAC 2 138 1040105 2350 2369 437069 437088 GCTCAGGTAGCCGATGACAG 84 2649 1040137 3185 3204 457438 457457 TCAGTTCGCCATTCTCAGAG 68 2650 1040169 3938 3957 458191 458210 AGCTGGGTTCCTGATGTTGA 45 2651 1040201 4488 4507 458741 458760 CAAAATCTAATTCCTCATGT 61 2652 1040233 4742 4761 458995 459014 TAGTTCATAATTCACATTCA 19 2653 1040265 5163 5182 459416 459435 CTCAGAGTTTCTAAGAGCCC 27 2654 1040297 5481 5500 459734 459753 AGTTGCAGCCATCCAAGTAA 26 2655 1040329 5914 5933 460167 460186 AGCCCGTATTCCTCTTACCA 22 2656 1040361 6269 6288 460522 460541 GGGAAGATCAACCAAACAAG 37 2657 1040393 7076 7095 461329 461348 GGTTTCTTATTAATAGTATT 23 2658 1040425 7575 7594 461828 461847 ACAACCCTACTCCAGAGCAG 59 2659 1040457 7976 7995 462229 462248 AACAGTAGCCATGACAACCA 80 2660 1040489 8317 8336 462570 462589 TGCCAGAAACACAACACTGT 88 2661 1040521 8668 8687 462921 462940 CATGTAACTTTCAACCCTTC 28 2662 1040553 9050 9069 463303 463322 TTTTGTCCCCATAATGAGTC 47 2663 1040585 9393 9412 463646 463665 ACATGAAAAACTGAAGCCGG 67 2664 1040617 9815 9834 464068 464087 CCTGGGCCAGAAAACTGAAA 131 2665 1040649 10226 10245 464479 464498 TTTCTTTTCAATAAGGTGCA 14 2666 1040681 10476 10495 464729 464748 CTAGAAAACCTGCAAGCACC 32 2667 1040713 N/A N/A 14562 14581 GCTGAATTTCAAACGCAGCA 96 2668 1040745 N/A N/A 28358 28377 GCAGTAATTTAAAGTATGAA 35 2669 1040777 N/A N/A 44806 44825 AACAAATTTTAAAGCTCTTT 36 2670 1040809 N/A N/A 75467 75486 AGCATCAACCAAATTCAGTA 20 2671 1040841 N/A N/A 91912 91931 CCCTGACCTATTTAACATAC 135 2672 1040873 N/A N/A 114340 114359 CTGTTTAACCAAAAACATCT 85 2673 1040905 N/A N/A 144629 144648 ATCACTAAACGATAGCACAA 102 2674 1040937 N/A N/A 172695 172714 AACTCCTTTTAAATTGAATT 111 2675 1040969 N/A N/A 193065 193084 GGGATTAAATAATTATGTGC 13 2676 1041001 N/A N/A 209950 209969 GCTAGCATATTTTAAAGAAG 138 2677 1041033 N/A N/A 233976 233995 CCAGCATTTCAAAGAGCAAC 69 2678 1041065 N/A N/A 256246 256265 GGCATGTTTATATAACAGCC 124 2679 1041097 N/A N/A 273626 273645 TTCCTAAAAGAATTTATCCA 108 2680 1041129 N/A N/A 291710 291729 GTTTCAATATTTTATGCAAA 3 2681 1041161 N/A N/A 322739 322758 GCAGTAATAATTTAGCCAAA 5 2682 1041193 N/A N/A 343540 343559 GCTATTAGACAATATAGAGT 2 2683 1041225 N/A N/A 369454 369473 CACTTCAAACCTTTATCAGT 30 2684 1041257 N/A N/A 389567 389586 AATCCTTTAATTTAACAACC 111 2685 1041289 N/A N/A 423903 423922 CCATGAAGAATTTAACCTCA 90 2686 1041321 N/A N/A 437795 437814 GGAGGTTAATTCATTACACA 6 2687 1041353 N/A N/A 438249 438268 TGGCCTTATCATACCTAAAT 80 2688 1041385 N/A N/A 438553 438572 ATTGATCACCCCAGCACCAG 88 2689 1041417 N/A N/A 439149 439168 TTACCCCAAGCCCAGCAGGT 95 2690 1041449 N/A N/A 439514 439533 CCCAAAACAATTCAAACCAT 69 2691 1041481 N/A N/A 440158 440177 ATTTTCTTTCTCCTAGTACC 69 2692 1041513 N/A N/A 440406 440425 AGAGGCTGCCAGGCCTGGGA 106 2693 1041545 N/A N/A 441288 441307 TGGAACCTCAATTAAGTCCA 75 2694 1041577 N/A N/A 441617 441636 ACCACCATACTATATCACAC 37 2695 1041609 N/A N/A 442257 442276 CCCTCAGTTTTATATGCCAT 17 2696 1041641 N/A N/A 442708 442727 ACTTATGGCCTCAAACTTGG 63 2697 1041673 N/A N/A 443057 443076 AAGTTCAGCCTTCTTTCTAG 28 2698 1041705 N/A N/A 443498 443517 AGCACTTTACCAATACATTT 46 2699 1041737 N/A N/A 443961 443980 ACTATCTATTTTTTGATACA 63 2700 1041769 N/A N/A 444350 444369 GTAACCAATCTATCACACCA 20 2701 1041801 N/A N/A 445255 445274 ATCCCACATTAAAAGCTGGG 121 2702 1041833 N/A N/A 445608 445627 GCATTCTTAACTTTGTCTGC 47 2703 1041865 N/A N/A 445874 445893 GTGCTATGTCTATATACACA 71 2704 1041897 N/A N/A 446067 446086 GGGCTCATAATTATTTTTTA 103 2705 1041929 N/A N/A 446685 446704 GAATAGCCTTTATAACTTTT 12 2706 1041961 N/A N/A 446928 446947 TCAGTTATTTTCTCTCCACT 9 2707 1041993 N/A N/A 447709 447728 CCTGCCAAAAAATCTTCTTC 127 2708 1042025 N/A N/A 448483 448502 TTGCTGGTTCTTTAACCCCT 31 2709 1042057 N/A N/A 448731 448750 CGGCTGTTCAATCAAGCACC 85 2710 1042089 N/A N/A 449073 449092 CCTCAAAATATTATTGAGGG 153 2711 1042121 N/A N/A 449627 449646 TGAAGAAATCTCACTGAGGG 149 2712 1042153 N/A N/A 449929 449948 AGATTATTCAGATAATCTGA 125 2713 1042185 N/A N/A 450548 450567 CCTTAGAATTAAATGCTGTG 84 2714 1042217 N/A N/A 451193 451212 TCCTCGATACTAACCCCTTC 93 2715 1042249 N/A N/A 451674 451693 TCAAAACTCCAAAGACACCA 67 2716 1042281 N/A N/A 451935 451954 GAGCCACATTATACACACTT 30 2717 1042313 N/A N/A 452254 452273 CCTCTTAGAGTCATTAACAA 62 2718 1042345 N/A N/A 452531 452550 AGTAGGATCCAAAGGCATGA 29 2719 1042377 N/A N/A 453048 453067 GTTCTGATACATTTCTAGAA 37 2720 1042409 N/A N/A 453856 453875 GAACTCACAGTTTACATCTC 53 2721 1042441 N/A N/A 454688 454707 TGTAGAATTAAAATATACAC 95 2722 1042473 N/A N/A 455314 455333 TGAGTCCCTAAAACTGGATT 112 2723 1042505 N/A N/A 456275 456294 TCCTTTCTAGATGTAGTAGA 25 2724 1042537 N/A N/A 456984 457003 GTTTGCAAACCTCCCTCTCC 101 2725

TABLE 37 Reduction of ATXN1 RNA by 5-10-5 MOE gapmers with mixed PO/PS linkages in A-431 Cells SEQ ID SEQ ID SEQ ID SEQ ID NO: 1 NO: 1 NO: 2 NO: 2 ATXN1 Compound Start Stop Start Stop (% SEQ Number Site Site Site Site Sequence (5′ to 3′) Control) ID NO 994605 N/A N/A 17726 17745 GTCACCTTTTCTATTTGCAC 3 138 1040106 2686 2705 437405 437424 GGAGCCTTTCATGAAGTAGG 28 2726 1040138 3195 3214 457448 457467 TCTGGAAACTTCAGTTCGCC 91 2727 1040170 3984 4003 458237 458256 TTAACTTTCCAAATCTGCCA 21 2728 1040202 4491 4510 458744 458763 CTTCAAAATCTAATTCCTCA 43 2729 1040234 4745 4764 458998 459017 TACTAGTTCATAATTCACAT 29 2730 1040266 5164 5183 459417 459436 TCTCAGAGTTTCTAAGAGCC 28 2731 1040298 5494 5513 459747 459766 ATTTGTTCAGTTTAGTTGCA 10 2732 1040330 5934 5953 460187 460206 GAGAACAAAGTCTATGTGGC 19 2733 1040362 6304 6323 460557 460576 GGCTCCTTCCCTCCAGCCCT 115 2734 1040394 7078 7097 461331 461350 TTGGTTTCTTATTAATAGTA 11 2735 1040426 7579 7598 461832 461851 TTGTACAACCCTACTCCAGA 78 2736 1040458 7985 8004 462238 462257 GGTTCATGAAACAGTAGCCA 93 2737 1040490 8319 8338 462572 462591 TATGCCAGAAACACAACACT 86 2738 1040522 8669 8688 462922 462941 ACATGTAACTTTCAACCCTT 29 2739 1040554 9051 9070 463304 463323 TTTTTGTCCCCATAATGAGT 34 2740 1040586 9396 9415 463649 463668 GGGACATGAAAAACTGAAGC 22 2741 1040618 9830 9849 464083 464102 AGGATTTACCCCACTCCTGG 82 2742 1040650 10228 10247 464481 464500 ATTTTCTTTTCAATAAGGTG 17 2743 1040682 10481 10500 464734 464753 TCTACCTAGAAAACCTGCAA 44 2744 1040714 N/A N/A 14865 14884 CTCACATTTTAAAGAGTCTG 41 2745 1040746 N/A N/A 29049 29068 TCACTGAACCCTTATTTTTT 30 2746 1040778 N/A N/A 46649 46668 ACTAGAAAAGCCACCCTTCT 129 2747 1040810 N/A N/A 76238 76257 AGTCTGTATATTTATATTTA 47 2748 1040842 N/A N/A 92036 92055 CCTTTGTTTTAAAATAGGTA 122 2749 1040874 N/A N/A 114410 114429 AATGCCAAAGATATACGCCA 6 2750 1040906 N/A N/A 145082 145101 AGTTAATATCCTTAATACAA 44 2751 1040938 N/A N/A 173470 173489 AAGTACTATCATTATTGCAT 113 2752 1040970 N/A N/A 193239 193258 TTCCCCTTATTTTATTCATA 63 2753 1041002 N/A N/A 210713 210732 TTCCTTCTAGATTAAAGACT 62 2754 1041034 N/A N/A 234265 234284 AACACAATTTAAATTGAGTT 127 2755 1041066 N/A N/A 256364 256383 CCTAAGTACCCTTAATTTTT 65 2756 1041098 N/A N/A 273876 273895 TGTCTATTTCAAAGAAGCGA 80 2757 1041130 N/A N/A 292765 292784 CACACAATTCAAAACTTGAA 93 2758 1041162 N/A N/A 322761 322780 AGCAGAATCTAAATCGAACA 22 2759 1041194 N/A N/A 343565 343584 CGTGTTTTTATTTAACAATA 2 2760 1041226 N/A N/A 369541 369560 ATTTCTTATATTTATGGGCT 3 2761 1041258 N/A N/A 391393 391412 TATAGTAGTATTTATAGCTC 28 2762 1041290 N/A N/A 424357 424376 ACCCCATTTCAAAGACAAGG 59 2763 1041322 N/A N/A 437796 437815 TGGAGGTTAATTCATTACAC 12 2764 1041354 N/A N/A 438250 438269 TTGGCCTTATCATACCTAAA 34 2765 1041386 N/A N/A 438574 438593 GTGCCCAGCCCTTCCACCTG 55 2766 1041418 N/A N/A 439153 439172 GACTTTACCCCAAGCCCAGC 98 2767 1041450 N/A N/A 439516 439535 TGCCCAAAACAATTCAAACC 94 2768 1041482 N/A N/A 440163 440182 AGTTCATTTTCTTTCTCCTA 5 2769 1041514 N/A N/A 440419 440438 GTCTGGTTTCTGCAGAGGCT 42 2770 1041546 N/A N/A 441292 441311 CCTTTGGAACCTCAATTAAG 89 2771 1041578 N/A N/A 441621 441640 TGTCACCACCATACTATATC 26 2772 1041610 N/A N/A 442258 442277 CCCCTCAGTTTTATATGCCA 45 2773 1041642 N/A N/A 442717 442736 GCGCCACAGACTTATGGCCT 142 2774 1041674 N/A N/A 443092 443111 GGCAGGGTAAAAATGGCTTA 52 2775 1041706 N/A N/A 443499 443518 GAGCACTTTACCAATACATT 23 2776 1041738 N/A N/A 443965 443984 ACCAACTATCTATTTTTTGA 51 2777 1041770 N/A N/A 444351 444370 TGTAACCAATCTATCACACC 30 2778 1041802 N/A N/A 445261 445280 ACACAAATCCCACATTAAAA 92 2779 1041834 N/A N/A 445611 445630 TGGGCATTCTTAACTTTGTC 28 2780 1041866 N/A N/A 445897 445916 TTGTATATTTCAATCTTAGA 26 2781 1041898 N/A N/A 446071 446090 TTCTGGGCTCATAATTATTT 52 2782 1041930 N/A N/A 446687 446706 TAGAATAGCCTTTATAACTT 33 2783 1041962 N/A N/A 446929 446948 TTCAGTTATTTTCTCTCCAC 16 2784 1041994 N/A N/A 447710 447729 TCCTGCCAAAAAATCTTCTT 118 2785 1042026 N/A N/A 448513 448532 ACTCCCTACACTGTAGCAAC 97 2786 1042058 N/A N/A 448749 448768 AATGGTATCCCATTCTTCCG 63 2787 1042090 N/A N/A 449075 449094 GGCCTCAAAATATTATTGAG 107 2788 1042122 N/A N/A 449649 449668 TTAACTGATCATTAACCGTT 49 2789 1042154 N/A N/A 449930 449949 AAGATTATTCAGATAATCTG 178 2790 1042186 N/A N/A 450550 450569 GGCCTTAGAATTAAATGCTG 145 2791 1042218 N/A N/A 451194 451213 CTCCTCGATACTAACCCCTT 118 2792 1042250 N/A N/A 451676 451695 TCTCAAAACTCCAAAGACAC 80 2793 1042282 N/A N/A 451937 451956 GTGAGCCACATTATACACAC 69 2794 1042314 N/A N/A 452263 452282 TCTTGCAAACCTCTTAGAGT 74 2795 1042346 N/A N/A 452544 452563 ATTGACTGAAATAAGTAGGA 16 2796 1042378 N/A N/A 453050 453069 TAGTTCTGATACATTTCTAG 47 2797 1042410 N/A N/A 453883 453902 CATATTATCTCCAAATAAGC 124 2798 1042442 N/A N/A 454701 454720 GGTCTATGAGAATTGTAGAA 32 2799 1042474 N/A N/A 455315 455334 CTGAGTCCCTAAAACTGGAT 78 2800 1042506 N/A N/A 456290 456309 AGTCAATTTCCAATGTCCTT 21 2801 1042538 N/A N/A 456985 457004 AGTTTGCAAACCTCCCTCTC 117 2802

TABLE 38 Reduction of ATXN1 RNA by 5-10-5 MOE gapmers with mixed PO/PS linkages in A-431 Cells SEQ ID SEQ ID SEQ ID SEQ ID NO: 1 NO: 1 NO: 2 NO: 2 ATXN1 Compound Start Stop Start Stop (% SEQ Number Site Site Site Site Sequence (5′ to 3′) Control) ID NO 994605 N/A N/A 17726 17745 GTCACCTTTTCTATTTGCAC 2 138 1040107 2687 2706 437406 437425 TGGAGCCTTTCATGAAGTAG 23 2803 1040139 3196 3215 457449 457468 CTCTGGAAACTTCAGTTCGC 87 2804 1040171 3985 4004 458238 458257 GTTAACTTTCCAAATCTGCC 23 2805 1040203 4493 4512 458746 458765 ATCTTCAAAATCTAATTCCT 45 2806 1040235 4746 4765 458999 459018 ATACTAGTTCATAATTCACA 35 2807 1040267 5172 5191 459425 459444 AAGAAAATTCTCAGAGTTTC 56 2808 1040299 5502 5521 459755 459774 AGTCAGGTATTTGTTCAGTT 5 2809 1040331 5952 5971 460205 460224 GTAAATAGTGATATTAATGA 53 2810 1040363 6365 6384 460618 460637 GCTCCCCGCCCCAGCACTCA 102 2811 1040395 7081 7100 461334 461353 TTGTTGGTTTCTTATTAATA 16 2812 1040427 7580 7599 461833 461852 ATTGTACAACCCTACTCCAG 70 2813 1040459 7987 8006 462240 462259 GTGGTTCATGAAACAGTAGC 88 2814 1040491 8321 8340 462574 462593 CCTATGCCAGAAACACAACA 72 2815 1040523 8683 8702 462936 462955 CTATATACAAAAAAACATGT 121 2816 1040555 9099 9118 463352 463371 CCCCCATTTAAATGAGGTGT 141 2817 1040587 9424 9443 463677 463696 CAGTTGAACCATTTGTATGC 22 2818 1040619 9842 9861 464095 464114 TGCACTAACTAAAGGATTTA 46 2819 1040651 10229 10248 464482 464501 AATTTTCTTTTCAATAAGGT 93 2820 1040683 10482 10501 464735 464754 TTCTACCTAGAAAACCTGCA 41 2821 1040715 N/A N/A 16686 16705 CTCGAAAAACATATCCCCCA 52 2822 1040747 N/A N/A 29088 29107 TGGTAATTTTAAAATATGGG 15 2823 1040779 N/A N/A 48578 48597 GTGTTAATTCAAAAAATTTC 119 2824 1040811 N/A N/A 76251 76270 TGCATACAAATTTAGTCTGT 21 2825 1040843 N/A N/A 93032 93051 TCTAGATTACAAACCATCCT 110 2826 1040875 N/A N/A 114768 114787 TTTCATTTTATTTAAGCCAA 20 2827 1040907 N/A N/A 146636 146655 AAGATGTTTTAAAATCTGAC 107 2828 1040939 N/A N/A 174742 174761 GTACTTGTTCCTTAACCAAG 149 2829 1040971 N/A N/A 193345 193364 TCAGTTTACCTTTAATGGAA 30 2830 1041003 N/A N/A 211774 211793 TGCTCAATATTTTAAACATT 44 2831 1041035 N/A N/A 234289 234308 GTCGGATAAATTTATCCACA 131 2832 1041067 N/A N/A 256544 256563 TTAGCAAACATTTATGAGCA 45 2833 1041099 N/A N/A 274538 274557 CTTCCAATCCATTACATCTT 81 2834 1041131 N/A N/A 293124 293143 CCTTCCAACCCTTAGCCTTT 12 2835 1041163 N/A N/A 323168 323187 AGCCAAAAACCCATGGACCA 120 2836 1041195 N/A N/A 343967 343986 ACAGTAATCTTTTATACAAG 19 2837 1041227 N/A N/A 369669 369688 TTCCCGAACCCTTAAGGATA 99 2838 1041259 N/A N/A 391405 391424 AGTTGACACCTTTATAGTAG 4 2839 1041291 N/A N/A 424646 424665 GTCTTAAAACTATTCACTGT 81 2840 1041323 N/A N/A 437820 437839 ATAACTAGCCCCACTCTCCA 98 2841 1041355 N/A N/A 438251 438270 GTTGGCCTTATCATACCTAA 21 2842 1041387 N/A N/A 438878 438897 GCTGCCTTCCATCTGTTTTT 90 2843 1041419 N/A N/A 439154 439173 TGACTTTACCCCAAGCCCAG 109 2844 1041451 N/A N/A 439554 439573 GAGACAAGAAACACTGTCTC 153 2845 1041483 N/A N/A 440171 440190 CTCAAGGTAGTTCATTTTCT 10 2846 1041515 N/A N/A 440723 440742 GCCTACAATCCCAGCTTTAG 88 2847 1041547 N/A N/A 441337 441356 GAGAAAACCCCTCAGGAAGG 115 2848 1041579 N/A N/A 441623 441642 TCTGTCACCACCATACTATA 57 2849 1041611 N/A N/A 442265 442284 CTAAACACCCCTCAGTTTTA 100 2850 1041643 N/A N/A 442722 442741 TGGATGCGCCACAGACTTAT 59 2851 1041675 N/A N/A 443093 443112 AGGCAGGGTAAAAATGGCTT 66 2852 1041707 N/A N/A 443502 443521 CCAGAGCACTTTACCAATAC 30 2853 1041739 N/A N/A 443966 443985 CACCAACTATCTATTTTTTG 47 2854 1041771 N/A N/A 444355 444374 CAGTTGTAACCAATCTATCA 22 2855 1041803 N/A N/A 445267 445286 CTCCTAACACAAATCCCACA 124 2856 1041835 N/A N/A 445625 445644 CGAAATTATTAAATTGGGCA 36 2857 1041867 N/A N/A 445899 445918 GATTGTATATTTCAATCTTA 55 2858 1041899 N/A N/A 446086 446105 ACAACACCGACTCACTTCTG 41 2859 1041931 N/A N/A 446708 446727 TCAAACACCCTAAGCAGTAA 74 2860 1041963 N/A N/A 446930 446949 CTTCAGTTATTTTCTCTCCA 10 2861 1041995 N/A N/A 447711 447730 ATCCTGCCAAAAAATCTTCT 100 2862 1042027 N/A N/A 448517 448536 CCTTACTCCCTACACTGTAG 99 2863 1042059 N/A N/A 448770 448789 ATGTTCTTCCCCATCTCCAT 36 2864 1042091 N/A N/A 449076 449095 CGGCCTCAAAATATTATTGA 165 2865 1042123 N/A N/A 449669 449688 GATATAAACATTCTTAAAGG 92 2866 1042155 N/A N/A 449932 449951 GGAAGATTATTCAGATAATC 24 2867 1042187 N/A N/A 450551 450570 AGGCCTTAGAATTAAATGCT 137 2868 1042219 N/A N/A 451198 451217 CAGTCTCCTCGATACTAACC 67 2869 1042251 N/A N/A 451677 451696 ATCTCAAAACTCCAAAGACA 87 2870 1042283 N/A N/A 451938 451957 TGTGAGCCACATTATACACA 69 2871 1042315 N/A N/A 452264 452283 CTCTTGCAAACCTCTTAGAG 99 2872 1042347 N/A N/A 452571 452590 TCCTGCTACCCCCCAACAGT 124 2873 1042379 N/A N/A 453088 453107 TTCATCTTCTTTGTTTCCTT 25 2874 1042411 N/A N/A 453892 453911 AACAAAATACATATTATCTC 99 2875 1042443 N/A N/A 454927 454946 CCGTTTCTACAGAAATTTAA 78 2876 1042475 N/A N/A 455316 455335 TCTGAGTCCCTAAAACTGGA 90 2877 1042507 N/A N/A 456620 456639 CCCAGCCCCTAAAAGGATGC 118 2878 1042539 N/A N/A 457035 457054 AGGTATGAACTCACACAGAC 63 2879

TABLE 39 Reduction of ATXN1 RNA by 5-10-5 MOE gapmers with mixed PO/PS linkages in A-431 Cells SEQ ID SEQ ID SEQ ID SEQ ID NO: 1 NO: 1 NO: 2 NO: 2 ATXN1 Compound Start Stop Start Stop (% SEQ Number Site Site Site Site Sequence (5′ to 3′) Control) ID NO 994605 N/A N/A 17726 17745 GTCACCTTTTCTATTTGCAC 2 138 1040108 2725 2744 437444 437463 TTCCACCTTCTTTAGCTCCC 67 2880 1040140 3212 3231 457465 457484 CAGGCAATCCCATTTTCTCT 84 2881 1040172 4000 4019 458253 458272 ATGTTCTTTTAAATGGTTAA 15 2882 1040204 4494 4513 458747 458766 CATCTTCAAAATCTAATTCC 66 2883 1040236 4749 4768 459002 459021 CACATACTAGTTCATAATTC 20 2884 1040268 5188 5207 459441 459460 TCTCTCAATGAATCTGAAGA 26 2885 1040300 5514 5533 459767 459786 GGGTAAAAGAAAAGTCAGGT 10 2886 1040332 5954 5973 460207 460226 TTGTAAATAGTGATATTAAT 74 2887 1040364 6439 6458 460692 460711 CTGCGGTTCCTCCCCCGGGT 124 2888 1040396 7117 7136 461370 461389 ATATATTTAGAAATCCCTAG 82 2889 1040428 7581 7600 461834 461853 AATTGTACAACCCTACTCCA 98 2890 1040460 8014 8033 462267 462286 GCAACAGACCAGTCTGTTGA 113 2891 1040492 8323 8342 462576 462595 TCCCTATGCCAGAAACACAA 70 2892 1040524 8684 8703 462937 462956 TCTATATACAAAAAAACATG 103 2893 1040556 9100 9119 463353 463372 CCCCCCATTTAAATGAGGTG 114 2894 1040588 9426 9445 463679 463698 TACAGTTGAACCATTTGTAT 67 2895 1040620 9862 9881 464115 464134 GCACAGGTATCAAGTTCAAA 17 2896 1040652 10235 10254 464488 464507 ACTTAAAATTTTCTTTTCAA 109 2897 1040684 10493 10512 464746 464765 AATGAAATAATTTCTACCTA 55 2898 1040716 N/A N/A 16822 16841 GGCACATTTTAAAAAGAAGC 23 2899 1040748 N/A N/A 30745 30764 TGTTTGCTATTTTAAGAGCC 24 2900 1040780 N/A N/A 48620 48639 GCTAGTAAAATTTAGGGCAG 36 2901 1040812 N/A N/A 76786 76805 TCTGAAAAACCTCTTCCTCT 60 2902 1040844 N/A N/A 93297 93316 GATGCATTTCATTACTGCTT 41 2903 1040876 N/A N/A 114844 114863 ATGTAATATTAAATAGCATC 70 2904 1040908 N/A N/A 148861 148880 AGGTAATTTCAAAGCTTCCA 4 2905 149972 149991 1040940 N/A N/A 175616 175635 CTTTCAATTCCTTAAAAGGA 101 2906 1040972 N/A N/A 195063 195082 ACACACAAAGAATGAACCAT 57 2907 1041004 N/A N/A 212966 212985 ATCCTAATTCAAAAACTAGT 131 2908 1041036 N/A N/A 235568 235587 AGCCATAAAACCATGCGGTT 91 2909 1041068 N/A N/A 256941 256960 TTACCCAAATTATCACTGTA 47 2910 1041100 N/A N/A 274711 274730 GGACTTAACCCTTACTCCAA 84 2911 1041132 N/A N/A 293412 293431 TGTTAGCTATTTTATATGGA 2 2912 1041164 N/A N/A 323174 323193 TTACACAGCCAAAAACCCAT 100 2913 1041196 N/A N/A 344505 344524 TGAGTAATTTAAAATGCCCA 43 2914 1041228 N/A N/A 369876 369895 AAGGTCTGCCTTTAACATTT 14 2915 1041260 N/A N/A 392003 392022 GTAAAATTTCTTTATGTGTG 4 2916 1041292 N/A N/A 424647 424666 AGTCTTAAAACTATTCACTG 78 2917 1041324 N/A N/A 437831 437850 TCAAGGACTCCATAACTAGC 111 2918 1041356 N/A N/A 438263 438282 GCTGATCTATCTGTTGGCCT 58 2919 1041388 N/A N/A 438882 438901 TAGGGCTGCCTTCCATCTGT 51 2920 1041420 N/A N/A 439156 439175 GCTGACTTTACCCCAAGCCC 100 2921 1041452 N/A N/A 439834 439853 AATGCTCAAAAAAGCCAGAC 54 2922 1041484 N/A N/A 440190 440209 CTGTGAAGAGTCAACTTTGC 65 2923 1041516 N/A N/A 440724 440743 CGCCTACAATCCCAGCTTTA 93 2924 1041548 N/A N/A 441358 441377 GGAAGATTCTTCAGGCTAGG 11 2925 1041580 N/A N/A 441624 441643 GTCTGTCACCACCATACTAT 34 2926 1041612 N/A N/A 442271 442290 CCCAAACTAAACACCCCTCA 97 2927 1041644 N/A N/A 442787 442806 AGCCCCATCCTTCTTTTGAG 88 2928 1041676 N/A N/A 443103 443122 CGAGGATTACAGGCAGGGTA 15 2929 1041708 N/A N/A 443511 443530 CGTGTCAACCCAGAGCACTT 120 2930 1041740 N/A N/A 443969 443988 AGTCACCAACTATCTATTTT 53 2931 1041772 N/A N/A 444356 444375 TCAGTTGTAACCAATCTATC 20 2932 1041804 N/A N/A 445269 445288 GCCTCCTAACACAAATCCCA 93 2933 1041836 N/A N/A 445626 445645 GCGAAATTATTAAATTGGGC 50 2934 1041868 N/A N/A 445900 445919 TGATTGTATATTTCAATCTT 114 2935 1041900 N/A N/A 446090 446109 GGAGACAACACCGACTCACT 81 2936 1041932 N/A N/A 446710 446729 TTTCAAACACCCTAAGCAGT 92 2937 1041964 N/A N/A 446938 446957 GAATCACACTTCAGTTATTT 19 2938 1041996 N/A N/A 447713 447732 CCATCCTGCCAAAAAATCTT 111 2939 1042028 N/A N/A 448519 448538 CCCCTTACTCCCTACACTGT 95 2940 1042060 N/A N/A 448773 448792 CCCATGTTCTTCCCCATCTC 70 2941 1042092 N/A N/A 449077 449096 CCGGCCTCAAAATATTATTG 114 2942 1042124 N/A N/A 449672 449691 AAGGATATAAACATTCTTAA 73 2943 1042156 N/A N/A 449935 449954 AGCGGAAGATTATTCAGATA 18 2944 1042188 N/A N/A 450567 450586 CCAAATCTCCAAAGACAGGC 54 2945 1042220 N/A N/A 451224 451243 ACTGGTGCCCAAATGTCTAT 54 2946 1042252 N/A N/A 451679 451698 GCATCTCAAAACTCCAAAGA 31 2947 1042284 N/A N/A 451940 451959 TGTGTGAGCCACATTATACA 86 2948 1042316 N/A N/A 452275 452294 CTCCATAGATCCTCTTGCAA 106 2949 1042348 N/A N/A 452589 452608 AAGAGATGAACTAAGCATTC 52 2950 1042380 N/A N/A 453101 453120 GTTGCTTTTCTACTTCATCT 21 2951 1042412 N/A N/A 453897 453916 TCTAGAACAAAATACATATT 131 2952 1042444 N/A N/A 455045 455064 ATCCATGAAGCCAGGCATGG 165 2953 1042476 N/A N/A 455318 455337 CATCTGAGTCCCTAAAACTG 93 2954 1042508 N/A N/A 456623 456642 GTCCCCAGCCCCTAAAAGGA 101 2955 1042540 N/A N/A 457036 457055 CAGGTATGAACTCACACAGA 56 2956

TABLE 40 Reduction of ATXN1 RNA by 5-10-5 MOE gapmers with mixed PO/PS linkages in A-431 Cells SEQ ID SEQ ID SEQ ID SEQ ID NO: 1 NO: 1 NO: 2 NO: 2 ATXN1 Compound Start Stop Start Stop (% SEQ Number Site Site Site Site Sequence (5′ to 3′) Control) ID NO 994605 N/A N/A 17726 17745 GTCACCTTTTCTATTTGCAC 3 138 1040109 2741 2760 437460 437479 CTTCTGTTTTTAAGTCTTCC 30 2957 1040141 3213 3232 457466 457485 GCAGGCAATCCCATTTTCTC 78 2958 1040173 4010 4029 458263 458282 GGAGAGAAAAATGTTCTTTT 5 2959 1040205 4497 4516 458750 458769 GCTCATCTTCAAAATCTAAT 9 2960 1040237 4758 4777 459011 459030 ATTTATTGTCACATACTAGT 76 2961 1040269 5216 5235 459469 459488 CACATATATAAATGTCTTTA 28 2962 1040301 5533 5552 459786 459805 GAAAGTACTATTTTCAATGG 27 2963 1040333 5959 5978 460212 460231 ATGAGTTGTAAATAGTGATA 22 2964 1040365 6440 6459 460693 460712 ACTGCGGTTCCTCCCCCGGG 111 2965 1040397 7126 7145 461379 461398 AGTCATTTTATATATTTAGA 58 2966 1040429 7601 7620 461854 461873 GAAATCCAAACATTCCTTGA 51 2967 1040461 8061 8080 462314 462333 GCCCTGTTTTCACCTGGTGC 57 2968 1040493 8325 8344 462578 462597 TTTCCCTATGCCAGAAACAC 63 2969 1040525 8685 8704 462938 462957 TTCTATATACAAAAAAACAT 107 2970 1040557 9101 9120 463354 463373 TCCCCCCATTTAAATGAGGT 145 2971 1040589 9439 9458 463692 463711 CACTTAATTTTAATACAGTT 44 2972 1040621 9883 9902 464136 464155 GCAGTATTCACAGAACTGAA 61 2973 1040653 10237 10256 464490 464509 GCACTTAAAATTTTCTTTTC 17 2974 1040685 10507 10526 464760 464779 TGTTTTATTATAATAATGAA 157 2975 1040717 N/A N/A 17529 17548 ACATCAAAACGATTTCTACT 25 2976 1040749 N/A N/A 31007 31026 AACCAAAACCAAAAGCCTCT 51 2977 1040781 N/A N/A 48839 48858 AATCTAAAATACATCTGCAT 103 2978 1040813 N/A N/A 77220 77239 CAGTTTATTTAAAGATATAA 119 2979 1040845 N/A N/A 94390 94409 ATCAGTAAAGAATTGATGTC 115 2980 1040877 N/A N/A 114917 114936 CTTCATAAAATTCCATTCTG 26 2981 1040909 N/A N/A 148914 148933 GCTTTCATAATATAACAACC 6 2982 150025 150044 1040941 N/A N/A 176494 176513 ATCAACAAAATTATGTATGG 124 2983 1040973 N/A N/A 195332 195351 GGAAACAACCAAAGTTTTTT 58 2984 1041005 N/A N/A 213451 213470 CTGTAGTTTTAAAAGTGCCT 15 2985 1041037 N/A N/A 236934 236953 ACCATATTTCTTTAGAAGGT 70 2986 1041069 N/A N/A 257007 257026 GTGACCAAAATACATATACT 47 2987 1041101 N/A N/A 274862 274881 ACTGGATTTATTTAAGTCTT 96 2988 1041133 N/A N/A 294752 294771 GAGTCTTGCCCTTAAGAAGC 4 2989 1041165 N/A N/A 323691 323710 TTGATATTTCAAAAGAGCTA 45 2990 1041197 N/A N/A 344706 344725 ATGTAAATATTTTAGCACAG 3 2991 1041229 N/A N/A 370271 370290 GACTAATTTTAAAATATGCT 36 2992 1041261 N/A N/A 392692 392711 GAGATAAAAATTATGTAGTT 86 2993 1041293 N/A N/A 425116 425135 TGGGATAATATTTATAAGTG 43 2994 1041325 N/A N/A 437884 437903 ATCTTAATCACAGAATTCAA 46 2995 1041357 N/A N/A 438268 438287 TGTCTGCTGATCTATCTGTT 14 2996 1041389 N/A N/A 438883 438902 TTAGGGCTGCCTTCCATCTG 58 2997 1041421 N/A N/A 439158 439177 CAGCTGACTTTACCCCAAGC 77 2998 1041453 N/A N/A 439844 439863 GCATTTAAGAAATGCTCAAA 132 2999 1041485 N/A N/A 440217 440236 GTTTATTTTCCATGTGTCAC 2 3000 1041517 N/A N/A 440772 440791 CTCCCCAAGAACAGAAGAGG 149 3001 1041549 N/A N/A 441359 441378 AGGAAGATTCTTCAGGCTAG 17 3002 1041581 N/A N/A 441646 441665 AGACCCAAATCCGCACCCCT 134 3003 1041613 N/A N/A 442273 442292 TCCCCAAACTAAACACCCCT 106 3004 1041645 N/A N/A 442814 442833 TACTTCCTACCCAAGGAGGA 124 3005 1041677 N/A N/A 443114 443133 GGATTCCACCCCGAGGATTA 120 3006 1041709 N/A N/A 443555 443574 CCCTAATAACACAGAGCCTG 113 3007 1041741 N/A N/A 443971 443990 GCAGTCACCAACTATCTATT 47 3008 1041773 N/A N/A 444357 444376 ATCAGTTGTAACCAATCTAT 16 3009 1041805 N/A N/A 445298 445317 TCAGTAAACCCACACCCTAG 109 3010 1041837 N/A N/A 445627 445646 GGCGAAATTATTAAATTGGG 100 3011 1041869 N/A N/A 445902 445921 TTTGATTGTATATTTCAATC 85 3012 1041901 N/A N/A 446109 446128 GATGGACGAACCTAGACAGG 54 3013 1041933 N/A N/A 446716 446735 ATCCTGTTTCAAACACCCTA 27 3014 1041965 N/A N/A 446945 446964 TTTTATTGAATCACACTTCA 41 3015 1041997 N/A N/A 447722 447741 TCCCTCTTCCCATCCTGCCA 89 3016 1042029 N/A N/A 448526 448545 GCATGTGCCCCTTACTCCCT 84 3017 1042061 N/A N/A 448774 448793 TCCCATGTTCTTCCCCATCT 72 3018 1042093 N/A N/A 449386 449405 AGCTTCAAAATATTGTTATT 53 3019 1042125 N/A N/A 449674 449693 ATAAGGATATAAACATTCTT 59 3020 1042157 N/A N/A 449937 449956 GGAGCGGAAGATTATTCAGA 33 3021 1042189 N/A N/A 450569 450588 CTCCAAATCTCCAAAGACAG 86 3022 1042221 N/A N/A 451237 451256 TTCTTGAACCCTCACTGGTG 100 3023 1042253 N/A N/A 451681 451700 CCGCATCTCAAAACTCCAAA 9 3024 1042285 N/A N/A 451942 451961 GGTGTGTGAGCCACATTATA 47 3025 1042317 N/A N/A 452277 452296 GGCTCCATAGATCCTCTTGC 95 3026 1042349 N/A N/A 452631 452650 TGACCTCTACCCTTGTGAGC 47 3027 1042381 N/A N/A 453102 453121 TGTTGCTTTTCTACTTCATC 73 3028 1042413 N/A N/A 453898 453917 CTCTAGAACAAAATACATAT 88 3029 1042445 N/A N/A 455059 455078 TCTGTTTTTAAAAGATCCAT 36 3030 1042477 N/A N/A 455353 455372 AACAGGCCTTTCAAGGTCTG 123 3031 1042509 N/A N/A 456640 456659 AGTGTGTTTATCACTGAGTC 97 3032 1042541 N/A N/A 457060 457079 CTTGTTTGATTTTATGCACA 92 3033

TABLE 41 Reduction of ATXN1 RNA by 5-10-5 MOE gapmers with mixed PO/PS linkages in A-431 Cells SEQ ID SEQ ID SEQ ID SEQ ID NO: 1 NO: 1 NO: 2 NO: 2 ATXN1 Compound Start Stop Start Stop (% SEQ Number Site Site Site Site Sequence (5′ to 3′) Control) ID NO 994605 N/A N/A 17726 17745 GTCACCTTTTCTATTTGCAC 2 138 1040110 2743 2762 437462 437481 ATCTTCTGTTTTTAAGTCTT 41 3034 1040142 3214 3233 457467 457486 TGCAGGCAATCCCATTTTCT 99 3035 1040174 4012 4031 458265 458284 TTGGAGAGAAAAATGTTCTT 23 3036 1040206 4499 4518 458752 458771 ATGCTCATCTTCAAAATCTA 23 3037 1040238 4763 4782 459016 459035 TGGTCATTTATTGTCACATA 6 3038 1040270 5220 5239 459473 459492 TGCTCACATATATAAATGTC 36 3039 1040302 5570 5589 459823 459842 GTTGATACCAGATTTTTTTT 30 3040 1040334 6015 6034 460268 460287 AGTCAATTCAATACTCGAAG 6 3041 1040366 6474 6493 460727 460746 TCCACATTCACTATTCCGTG 17 3042 1040398 7128 7147 461381 461400 ACAGTCATTTTATATATTTA 34 3043 1040430 7604 7623 461857 461876 CAGGAAATCCAAACATTCCT 130 3044 1040462 8106 8125 462359 462378 TCACATCACCACCGAAGAAA 40 3045 1040494 8331 8350 462584 462603 TTGGAGTTTCCCTATGCCAG 17 3046 1040526 8692 8711 462945 462964 GACAAATTTCTATATACAAA 57 3047 1040558 9103 9122 463356 463375 ACTCCCCCCATTTAAATGAG 116 3048 1040590 9440 9459 463693 463712 GCACTTAATTTTAATACAGT 15 3049 1040622 9884 9903 464137 464156 GGCAGTATTCACAGAACTGA 41 3050 1040654 10253 10272 464506 464525 CTTAACTATTATGTATGCAC 17 3051 1040686 10508 10527 464761 464780 TTGTTTTATTATAATAATGA 195 3052 1040718 N/A N/A 17546 17565 GCAGGTAAAACCAAATGACA 121 3053 1040750 N/A N/A 31009 31028 GCAACCAAAACCAAAAGCCT 67 3054 1040782 N/A N/A 49205 49224 GGGCTATTAATTTATTAAAT 123 3055 1040814 N/A N/A 77279 77298 AAGATCTTTTAAAGTCCTAC 58 3056 1040846 N/A N/A 94692 94711 GTAAGCTCCATTTATAGAAT 30 3057 1040878 N/A N/A 117437 117456 CCTCACACACCTTAACCCTG 95 3058 1040910 N/A N/A 151015 151034 GAGATAAAAATTATTTTGGC 108 3059 1040942 N/A N/A 176706 176725 GCTAAATTTCATTAGAAACA 115 3060 1040974 N/A N/A 195854 195873 TTTTCTACAATTTATAGGCG 27 3061 1041006 N/A N/A 215585 215604 CTGCACCAAATTTATTTTTG 37 3062 1041038 N/A N/A 237026 237045 ACTGAAAAAACTGTATGATC 99 3063 1041070 N/A N/A 257572 257591 CCTTTTAAAATTTCCAGAAA 97 3064 1041102 N/A N/A 276104 276123 GAAGTTAGCCAGGCATCAGG 77 3065 1041134 N/A N/A 294914 294933 GCAGAGTTTTAAAATGCACT 14 3066 1041166 N/A N/A 324245 324264 AGGCATAGTATTTAGCAGAA 2 3067 1041198 N/A N/A 345616 345635 TACTTCTTTCCTTAAGCACA 6 3068 1041230 N/A N/A 370434 370453 TAGTTTAAAATATGTGACTC 96 3069 1041262 N/A N/A 393162 393181 CCAGAAAAACCTTAAACTAC 73 3070 1041294 N/A N/A 425225 425244 ACCTTCAAACTATCAATTCT 105 3071 1041326 N/A N/A 437890 437909 TTCCTCATCTTAATCACAGA 25 3072 1041358 N/A N/A 438300 438319 GAGAGTATAAAAATTATCTC 102 3073 1041390 N/A N/A 438894 438913 GTCCATCACACTTAGGGCTG 37 3074 1041422 N/A N/A 439161 439180 CTACAGCTGACTTTACCCCA 50 3075 1041454 N/A N/A 439848 439867 TTGGGCATTTAAGAAATGCT 116 3076 1041486 N/A N/A 440219 440238 ATGTTTATTTTCCATGTGTC 3 3077 1041518 N/A N/A 440776 440795 CTTCCTCCCCAAGAACAGAA 88 3078 1041550 N/A N/A 441384 441403 CAGTGCCTAACCAGTTGAGA 28 3079 1041582 N/A N/A 441650 441669 CCAGAGACCCAAATCCGCAC 65 3080 1041614 N/A N/A 442275 442294 CATCCCCAAACTAAACACCC 95 3081 1041646 N/A N/A 442820 442839 CTAACCTACTTCCTACCCAA 133 3082 1041678 N/A N/A 443164 443183 AGCCTTAGAAACAGGAACGG 46 3083 1041710 N/A N/A 443556 443575 GCCCTAATAACACAGAGCCT 142 3084 1041742 N/A N/A 444005 444024 CGGCACAAATCCAGGGCTGG 87 3085 1041774 N/A N/A 444387 444406 TAGTTAAAAATAAGGTATCG 87 3086 1041806 N/A N/A 445299 445318 TTCAGTAAACCCACACCCTA 110 3087 1041838 N/A N/A 445628 445647 TGGCGAAATTATTAAATTGG 102 3088 1041870 N/A N/A 445919 445938 CACGCATATTTATGCTGTTT 86 3089 1041902 N/A N/A 446110 446129 GGATGGACGAACCTAGACAG 34 3090 1041934 N/A N/A 446718 446737 ATATCCTGTTTCAAACACCC 43 3091 1041966 N/A N/A 446947 446966 GATTTTATTGAATCACACTT 19 3092 1041998 N/A N/A 447903 447922 CAACCATTCCAGACTGAGCT 109 3093 1042030 N/A N/A 448548 448567 ACATGCAAGCCTGATGTGGT 121 3094 1042062 N/A N/A 448818 448837 CTAAAACACACCAGACCTCC 91 3095 1042094 N/A N/A 449387 449406 TAGCTTCAAAATATTGTTAT 62 3096 1042126 N/A N/A 449684 449703 TAGGTTTGTCATAAGGATAT 11 3097 1042158 N/A N/A 449978 449997 GCCACGACCAGATATCAGCT 39 3098 1042190 N/A N/A 450570 450589 ACTCCAAATCTCCAAAGACA 95 3099 1042222 N/A N/A 451238 451257 CTTCTTGAACCCTCACTGGT 119 3100 1042254 N/A N/A 451682 451701 TCCGCATCTCAAAACTCCAA 28 3101 1042286 N/A N/A 451968 451987 GGACACCTACCCATGGAGAG 57 3102 1042318 N/A N/A 452311 452330 ACTGTATTCTAAGTAGGAGG 23 3103 1042350 N/A N/A 452636 452655 CCTCCTGACCTCTACCCTTG 77 3104 1042382 N/A N/A 453115 453134 GATTTCCACAGATTGTTGCT 66 3105 1042414 N/A N/A 453899 453918 CCTCTAGAACAAAATACATA 36 3106 1042446 N/A N/A 455060 455079 ATCTGTTTTTAAAAGATCCA 71 3107 1042478 N/A N/A 455364 455383 AACCACAAGCCAACAGGCCT 114 3108 1042510 N/A N/A 456663 456682 TGTGAGTTCCAAGAAGCAGG 54 3109 1042542 N/A N/A 457069 457088 CATTTTATTCTTGTTTGATT 149 3110

TABLE 42 Reduction of ATXN1 RNA by 5-10-5 MOE gapmers with mixed PO/PS linkages in A-431 Cells SEQ ID SEQ ID SEQ ID SEQ ID NO: 1 NO: 1 NO: 2 NO: 2 ATXN1 Compound Start Stop Start Stop (% SEQ Number Site Site Site Site Sequence (5′ to 3′) Control) ID NO 994605 N/A N/A 17726 17745 GTCACCTTTTCTATTTGCAC 2 138 994630 N/A N/A 85516 85535 GTTTGATATGCTATGCTCAC 12 219 994693 N/A N/A 184184 184203 TCAGGTTTATATGTATACAA 2 149 994706 N/A N/A 217284 217303 GTTATGTTTAAGGTATTTTC 5 540 994735 N/A N/A 297005 297024 GTTTGCATTAAATGACTGTG 1 310 1054946 101 120 2611 2630 CTGTTGCTCTGGCTGCTGCT 10 3111 1054950 110 129 2620 2639 TTGCGGCTGCTGTTGCTCTG 14 3112 1054955 117 136 2627 2646 CAATGTCTTGCGGCTGCTGT 24 3113 1054966 248 267 10659 10678 CCTGGTGACTTGATGCACGA 25 3114 1054972 552 571 178162 178181 ATCAGTTCCTTGCAGCAGAT 3 3115 1054978 561 580 178171 178190 CCATAAGCTATCAGTTCCTT 2 3116 1054983 568 587 178178 178197 TGGAGAACCATAAGCTATCA 8 3117 1054989 586 605 178196 178215 CATGTGCTTTCATCACAATG 63 3118 1054994 592 611 178202 178221 CTGTACCATGTGCTTTCATC 2 3119 1055000 3487 3506 457740 457759 TAAATACTGTGTTATTTTAG 72 3120 1055004 5497 5516 459750 459769 GGTATTTGTTCAGTTTAGTT 6 3121 1055008 5503 5522 459756 459775 AAGTCAGGTATTTGTTCAGT 5 3122 1055014 6028 6047 460281 460300 GTTTAGTGGATCCAGTCAAT 16 3123 1055018 6035 6054 460288 460307 AGTGTTGGTTTAGTGGATCC 32 3124 1055023 6044 6063 460297 460316 TCCCATCTTAGTGTTGGTTT 28 3125 1055029 9484 9503 463737 463756 TTAGAGATTGTTGTTATTGT 13 3126 1055034 9490 9509 463743 463762 AAATTCTTAGAGATTGTTGT 14 3127 1055039 10090 10109 464343 464362 TGATCTGATATTAAAACATC 78 3128 1055044 10097 10116 464350 464369 TGGGTAATGATCTGATATTA 13 3129 1055050 10106 10125 464359 464378 GGCATATGGTGGGTAATGAT 12 3130 1055056 196 215 9912 9931 AGTAGTTTTTGTGAGGTAAA 11 3131 1055060 202 221 9918 9937 GCTTGTAGTAGTTTTTGTGA 29 3132 1055064 N/A N/A 17720 17739 TTTTCTATTTGCACTAGCTG 65 3133 1055070 N/A N/A 17728 17747 ATGTCACCTTTTCTATTTGC 3 3134 1055076 N/A N/A 24689 24708 AAACACTAGAAATCCAGGGA 7 3135 1055082 N/A N/A 85508 85527 TGCTATGCTCACAGAGAACC 78 3136 1055093 N/A N/A 85524 85543 TACAGTTAGTTTGATATGCT 25 3137 1055098 N/A N/A 108194 108213 GGAATAAATTATTTACTGCG 5 3138 1055104 N/A N/A 148323 148342 TACTATGTATTTGCCACAGT 6 3139 149434 149453 1055110 N/A N/A 179786 179805 ATATTTAATCATGTTCCCGA 13 3140 1055115 N/A N/A 179792 179811 ATAGTTATATTTAATCATGT 67 3141 1055120 N/A N/A 184176 184195 ATATGTATACAATTCTGACA 38 3142 1055131 N/A N/A 184192 184211 CAATGTTCTCAGGTTTATAT 15 3143 1055137 N/A N/A 203033 203052 CCTTTCTTCTTTGTTCATAG 6 3144 1055142 N/A N/A 203039 203058 CTTGTTCCTTTCTTCTTTGT 31 3145 1055148 N/A N/A 203883 203902 ATTTATCCTCAGGATGCAAA 55 3146 1055154 N/A N/A 203892 203911 TTTGTTTAGATTTATCCTCA 6 3147 1055159 N/A N/A 210724 210743 ATACTCCATTTTTCCTTCTA 19 3148 1055164 N/A N/A 210731 210750 ATGTGTAATACTCCATTTTT 25 3149 1055170 N/A N/A 210740 210759 TTATTACAAATGTGTAATAC 107 3150 1055176 N/A N/A 212029 212048 TATGTTAGTCATTTCTCTCT 28 3151 1055181 N/A N/A 212035 212054 CAAGTCTATGTTAGTCATTT 10 3152 1055187 N/A N/A 217276 217295 TAAGGTATTTTCATGGAGTT 12 3153 1055198 N/A N/A 217292 217311 TTGTAACAGTTATGTTTAAG 43 3154 1055204 N/A N/A 226990 227009 TTTACTCATTCTACCTTCAA 66 3155 1055209 N/A N/A 226997 227016 TTGGTTATTTACTCATTCTA 20 3156 1055215 N/A N/A 227006 227025 TCCATAAACTTGGTTATTTA 25 3157 1055221 N/A N/A 251494 251513 TTAGCTTTTCAAATACTAAA 91 3158 1055227 N/A N/A 251503 251522 TCAGCATACTTAGCTTTTCA 11 3159 1055232 N/A N/A 251510 251529 GACAGTGTCAGCATACTTAG 12 3160 1055238 N/A N/A 273793 273812 TACCCAGGTTATTACACTGT 116 3161 1055244 N/A N/A 284229 284248 TTGGGTTTTTCTGTACAAAG 1 3162 1055249 N/A N/A 284235 284254 TTTTGTTTGGGTTTTTCTGT 1 3163 1055255 N/A N/A 284335 284354 CTAGTTCTTATCACTATTCA 7 3164 1055260 N/A N/A 284342 284361 ATGTCAACTAGTTCTTATCA 5 3165 1055266 N/A N/A 284351 284370 GACTAAACAATGTCAACTAG 12 3166 1055272 N/A N/A 291011 291030 TGGGTTTTTAGTTTTCCTTC 4 3167 1055277 N/A N/A 291017 291036 AGGTCCTGGGTTTTTAGTTT 3 3168 1055283 N/A N/A 296997 297016 TAAATGACTGTGGTGCAGCC 9 3169 1055294 N/A N/A 297013 297032 AAGCCAGTGTTTGCATTAAA 1 3170 1055300 N/A N/A 306737 306756 AAGGGCCACTAAATCTGACC 22 3171 1055306 N/A N/A 318477 318496 ATTTCTTTTTTTTTTAAGTT 103 3172 1055311 N/A N/A 318486 318505 GTGTTTGATATTTCTTTTTT 1 3173 1055317 N/A N/A 318495 318514 CTTTCAAATGTGTTTGATAT 3 3174 1055323 N/A N/A 332356 332375 TTATAACAATTTGCATAGTC 4 3175 1055328 N/A N/A 332363 332382 GGGAGTATTATAACAATTTG 1 3176 1055334 N/A N/A 332372 332391 TATTTTCCAGGGAGTATTAT 36 3177 1055340 N/A N/A 347819 347838 CATTATCTAGTTTCTGGAAA 28 3178 1055345 N/A N/A 347825 347844 AATGGTCATTATCTAGTTTC 7 3179 1055351 N/A N/A 353593 353612 CTAAATCTGACTTACAAAGG 121 3180 1055357 N/A N/A 377459 377478 TAAAACCAATACATTAACAT 117 3181 1055363 N/A N/A 410197 410216 CATTATGCTTTAAGATCACA 5 3182

TABLE 43 Reduction of ATXN1 RNA by 5-10-5 MOE gapmers with mixed PO/PS linkages in A-431 Cells SEQ ID SEQ ID SEQ ID SEQ ID NO: 1 NO: 1 NO: 2 NO: 2 ATXN1 SEQ Compound Start Stop Start Stop (% ID Number Site Site Site Site Sequence (5′ to 3′) Control) NO 994311 103 122 2613 2632 TGCTGTTGCTCTGGCTGCTG 33 257 994313 111 130 2621 2640 CTTGCGGCTGCTGTTGCTCT 14 413 994328 562 581 178172 178191 ACCATAAGCTATCAGTTCCT 2 337 994599 204 223 9920 9939 GTGCTTGTAGTAGTTTTTGT 23 293 994605 N/A N/A 17726 17745 GTCACCTTTTCTATTTGCAC 1 138 994701 N/A N/A 203893 203912 GTTTGTTTAGATTTATCCTC 2 150 994717 N/A N/A 251504 251523 GTCAGCATACTTAGCTTTTC 8 152 1040945 N/A N/A 179793 179812 CATAGTTATATTTAATCATG 52 828 1054956 119 138 2629 2648 AACAATGTCTTGCGGCTGCT 24 3183 1054962 243 262 10654 10673 TGACTTGATGCACGATGCTC 10 3184 1054967 249 268 10660 10679 CCCTGGTGACTTGATGCACG 23 3185 1054973 554 573 178164 178183 CTATCAGTTCCTTGCAGCAG 3 3186 1054984 570 589 178180 178199 AATGGAGAACCATAAGCTAT 26 3187 1054990 587 606 178197 178216 CCATGTGCTTTCATCACAAT 20 3188 1054995 593 612 N/A N/A ACTGTACCATGTGCTTTCAT 1 3189 1055001 5489 5508 459742 459761 TTCAGTTTAGTTGCAGCCAT 7 3190 1055005 5498 5517 459751 459770 AGGTATTTGTTCAGTTTAGT 7 3191 1055009 5505 5524 459758 459777 AAAAGTCAGGTATTTGTTCA 15 3192 1055015 6030 6049 460283 460302 TGGTTTAGTGGATCCAGTCA 18 3193 1055019 6036 6055 460289 460308 TAGTGTTGGTTTAGTGGATC 23 3194 1055024 9476 9495 463729 463748 TGTTGTTATTGTATAGATAC 9 3195 1055030 9485 9504 463738 463757 CTTAGAGATTGTTGTTATTG 15 3196 1055035 9492 9511 463745 463764 GGAAATTCTTAGAGATTGTT 12 3197 1055040 10092 10111 464345 464364 AATGATCTGATATTAAAACA 43 3198 1055045 10098 10117 464351 464370 GTGGGTAATGATCTGATATT 13 3199 1055051 188 207 N/A N/A TTGTGAGGTAAAACTGTAAA 137 3200 1055057 197 216 9913 9932 TAGTAGTTTTTGTGAGGTAA 12 3201 1055065 N/A N/A 17722 17741 CCTTTTCTATTTGCACTAGC 28 3202 1055071 N/A N/A 17729 17748 AATGTCACCTTTTCTATTTG 16 3203 1055077 N/A N/A 36482 36501 AACTCTCTTAAGTACTTATA 16 3204 1055083 N/A N/A 85510 85529 TATGCTATGCTCACAGAGAA 55 3205 1055088 N/A N/A 85517 85536 AGTTTGATATGCTATGCTCA 8 3206 1055094 N/A N/A 85526 85545 CTTACAGTTAGTTTGATATG 26 3207 1055099 N/A N/A 125427 125446 AGCTTCCAGATAAAACCTCC 61 3208 1055105 N/A N/A 179272 179291 TTCAAAATTCTCAGCATTGG 5 3209 1055111 N/A N/A 179787 179806 TATATTTAATCATGTTCCCG 13 3210 1055121 N/A N/A 184178 184197 TTATATGTATACAATTCTGA 67 3211 1055126 N/A N/A 184185 184204 CTCAGGTTTATATGTATACA 1 3212 1055132 N/A N/A 184194 184213 GGCAATGTTCTCAGGTTTAT 1 3213 1055138 N/A N/A 203034 203053 TCCTTTCTTCTTTGTTCATA 9 3214 1055143 N/A N/A 203040 203059 TCTTGTTCCTTTCTTCTTTG 20 3215 1055149 N/A N/A 203885 203904 AGATTTATCCTCAGGATGCA 26 3216 1055160 N/A N/A 210726 210745 TAATACTCCATTTTTCCTTC 25 3217 1055165 N/A N/A 210732 210751 AATGTGTAATACTCCATTTT 51 3218 1055171 N/A N/A 212021 212040 TCATTTCTCTCTGGCTGTGC 27 3219 1055177 N/A N/A 212030 212049 CTATGTTAGTCATTTCTCTC 15 3220 1055182 N/A N/A 212037 212056 ATCAAGTCTATGTTAGTCAT 11 3221 1055188 N/A N/A 217278 217297 TTTAAGGTATTTTCATGGAG 7 3222 1055193 N/A N/A 217285 217304 AGTTATGTTTAAGGTATTTT 53 3223 1055199 N/A N/A 217294 217313 ACTTGTAACAGTTATGTTTA 44 3224 1055205 N/A N/A 226992 227011 TATTTACTCATTCTACCTTC 63 3225 1055210 N/A N/A 226998 227017 CTTGGTTATTTACTCATTCT 21 3226 1055216 N/A N/A 228677 228696 GGCTGATTCTAGTACTGTGA 51 3227 1055222 N/A N/A 251496 251515 ACTTAGCTTTTCAAATACTA 30 3228 1055233 N/A N/A 251512 251531 AGGACAGTGTCAGCATACTT 14 3229 1055239 N/A N/A 284221 284240 TTCTGTACAAAGTTCAGTTG 54 3230 1055245 N/A N/A 284230 284249 TTTGGGTTTTTCTGTACAAA <1 3231 1055250 N/A N/A 284237 284256 AGTTTTGTTTGGGTTTTTCT <1 3232 1055256 N/A N/A 284337 284356 AACTAGTTCTTATCACTATT 37 3233 1055261 N/A N/A 284343 284362 AATGTCAACTAGTTCTTATC 2 3234 1055267 N/A N/A 288842 288861 TATAAAATTCACCTAAAATT 110 3235 1055273 N/A N/A 291012 291031 CTGGGTTTTTAGTTTTCCTT 1 3236 1055278 N/A N/A 291018 291037 TAGGTCCTGGGTTTTTAGTT 3 3237 1055284 N/A N/A 296999 297018 ATTAAATGACTGTGGTGCAG 3 3238 1055289 N/A N/A 297006 297025 TGTTTGCATTAAATGACTGT 27 3239 1055295 N/A N/A 297015 297034 AAAAGCCAGTGTTTGCATTA 2 3240 1055301 N/A N/A 306738 306757 TAAGGGCCACTAAATCTGAC 12 3241 306824 306843 1055307 N/A N/A 318479 318498 ATATTTCTTTTTTTTTTAAG 134 3242 1055312 N/A N/A 318487 318506 TGTGTTTGATATTTCTTTTT <1 3243 1055318 N/A N/A 318632 318651 ATGCAAGGTCCAGGGAATAC 1 3244 1055324 N/A N/A 332358 332377 TATTATAACAATTTGCATAG 46 3245 1055329 N/A N/A 332364 332383 AGGGAGTATTATAACAATTT 1 3246 1055335 N/A N/A 333552 333571 TATGAGTAATTAGCACAAAG 11 3247 1055341 N/A N/A 347820 347839 TCATTATCTAGTTTCTGGAA 6 3248 1055346 N/A N/A 347826 347845 AAATGGTCATTATCTAGTTT 5 3249 1055352 N/A N/A 353767 353786 ACTTCCAATTTTGAAATACT 10 3250 1055358 N/A N/A 389235 389254 GAAAGCCCCAGCACATAAAT 114 3251 1055364 N/A N/A 420350 420369 TGAAAGCTGGCCGATATCCC 65 3252

TABLE 44 Reduction of ATXN1 RNA by 5-10-5 MOE gapmers with mixed PO/PS linkages in A-431 Cells SEQ ID SEQ ID SEQ ID SEQ ID NO: 1 NO: 1 NO: 2 NO: 2 ATXN1 Compound Start Stop Start Stop (% SEQ Number Site Site Site Site Sequence (5′ to 3′) Control) ID NO 994312 105 124 2615 2634 GCTGCTGTTGCTCTGGCTGC 48 335 994447 5491 5510 459744 459763 TGTTCAGTTTAGTTGCAGCC 12 274 994449 5499 5518 459752 459771 CAGGTATTTGTTCAGTTTAG 8 430 994561 9486 9505 463739 463758 TCTTAGAGATTGTTGTTATT 13 444 994597 198 217 9914 9933 GTAGTAGTTTTTGTGAGGTA 10 137 994601 206 225 9922 9941 TGGTGCTTGTAGTAGTTTTT 31 449 994605 N/A N/A 17726 17745 GTCACCTTTTCTATTTGCAC 2 138 994703 N/A N/A 212031 212050 TCTATGTTAGTCATTTCTCT 21 306 994731 N/A N/A 284231 284250 GTTTGGGTTTTTCTGTACAA 2 621 1040848 N/A N/A 96129 96148 CACTTTCTAGATTATTCTTA 102 748 1054951 112 131 2622 2641 TCTTGCGGCTGCTGTTGCTC 14 3253 1054957 121 140 2631 2650 GAAACAATGTCTTGCGGCTG 15 3254 1054963 244 263 10655 10674 GTGACTTGATGCACGATGCT 8 3255 1054968 250 269 10661 10680 ACCCTGGTGACTTGATGCAC 20 3256 1054974 556 575 178166 178185 AGCTATCAGTTCCTTGCAGC 11 3257 1054979 563 582 178173 178192 AACCATAAGCTATCAGTTCC 7 3258 1054985 572 591 178182 178201 ACAATGGAGAACCATAAGCT 101 3259 1054991 588 607 178198 178217 ACCATGTGCTTTCATCACAA 3 3260 1054996 594 613 N/A N/A AACTGTACCATGTGCTTTCA 3 3261 1055010 5507 5526 459760 459779 AGAAAAGTCAGGTATTTGTT 14 3262 1055016 6031 6050 460284 460303 TTGGTTTAGTGGATCCAGTC 31 3263 1055020 6037 6056 460290 460309 TTAGTGTTGGTTTAGTGGAT 20 3264 1055025 9478 9497 463731 463750 ATTGTTGTTATTGTATAGAT 18 3265 1055036 9494 9513 463747 463766 ATGGAAATTCTTAGAGATTG 16 3266 1055041 10093 10112 464346 464365 TAATGATCTGATATTAAAAC 111 3267 1055046 10099 10118 464352 464371 GGTGGGTAATGATCTGATAT 34 3268 1055052 190 209 N/A N/A TTTTGTGAGGTAAAACTGTA 136 3269 1055066 N/A N/A 17723 17742 ACCTTTTCTATTTGCACTAG 19 3270 1055072 N/A N/A 17730 17749 AAATGTCACCTTTTCTATTT 56 3271 1055078 N/A N/A 36986 37005 GCTATTTTTTCCAGAAAGTC 6 3272 1055084 N/A N/A 85512 85531 GATATGCTATGCTCACAGAG 23 3273 1055089 N/A N/A 85518 85537 TAGTTTGATATGCTATGCTC 33 3274 1055100 N/A N/A 133992 134011 AATTTTTTTTAACATCTTGC 88 3275 1055106 N/A N/A 179779 179798 ATCATGTTCCCGATATTGGA 15 3276 1055112 N/A N/A 179788 179807 TTATATTTAATCATGTTCCC 11 3277 1055116 N/A N/A 179795 179814 AACATAGTTATATTTAATCA 132 3278 1055122 N/A N/A 184180 184199 GTTTATATGTATACAATTCT 26 3279 1055127 N/A N/A 184186 184205 TCTCAGGTTTATATGTATAC 4 3280 1055133 N/A N/A 187811 187830 TCACAGGGAATAATGAAGAG 73 3281 1055139 N/A N/A 203035 203054 TTCCTTTCTTCTTTGTTCAT 45 3282 1055144 N/A N/A 203041 203060 CTCTTGTTCCTTTCTTCTTT 20 3283 1055150 N/A N/A 203887 203906 TTAGATTTATCCTCAGGATG 51 3284 1055155 N/A N/A 203894 203913 GGTTTGTTTAGATTTATCCT 11 3285 1055161 N/A N/A 210727 210746 GTAATACTCCATTTTTCCTT 4 3286 1055166 N/A N/A 210733 210752 AAATGTGTAATACTCCATTT 53 3287 1055172 N/A N/A 212023 212042 AGTCATTTCTCTCTGGCTGT 53 3288 1055183 N/A N/A 212039 212058 AAATCAAGTCTATGTTAGTC 63 3289 1055189 N/A N/A 217280 217299 TGTTTAAGGTATTTTCATGG 8 3290 1055194 N/A N/A 217286 217305 CAGTTATGTTTAAGGTATTT 19 3291 1055200 N/A N/A 222603 222622 CTGTTCTTAGCTTCCCAGCT 39 3292 1055206 N/A N/A 226993 227012 TTATTTACTCATTCTACCTT 82 3293 1055211 N/A N/A 226999 227018 ACTTGGTTATTTACTCATTC 17 3294 1055217 N/A N/A 230285 230304 AATCTCCAGTTATGAGTAAG 82 3295 1055223 N/A N/A 251498 251517 ATACTTAGCTTTTCAAATAC 83 3296 1055228 N/A N/A 251505 251524 TGTCAGCATACTTAGCTTTT 32 3297 1055234 N/A N/A 251514 251533 CCAGGACAGTGTCAGCATAC 29 3298 1055240 N/A N/A 284223 284242 TTTTCTGTACAAAGTTCAGT 4 3299 1055251 N/A N/A 284239 284258 TTAGTTTTGTTTGGGTTTTT 2 3300 1055257 N/A N/A 284338 284357 CAACTAGTTCTTATCACTAT 15 3301 1055262 N/A N/A 284344 284363 CAATGTCAACTAGTTCTTAT 4 3302 1055268 N/A N/A 291004 291023 TTAGTTTTCCTTCTTGTCTT 7 3303 1055274 N/A N/A 291013 291032 CCTGGGTTTTTAGTTTTCCT 3 3304 1055279 N/A N/A 291020 291039 ATTAGGTCCTGGGTTTTTAG 3 3305 1055285 N/A N/A 297001 297020 GCATTAAATGACTGTGGTGC 5 3306 1055290 N/A N/A 297007 297026 GTGTTTGCATTAAATGACTG 4 3307 1055296 N/A N/A 306730 306749 ACTAAATCTGACCTTCCTCA 35 3308 1055302 N/A N/A 306741 306760 TGGTAAGGGCCACTAAATCT 4 3309 306827 306846 1055308 N/A N/A 318481 318500 TGATATTTCTTTTTTTTTTA 104 3310 1055313 N/A N/A 318488 318507 ATGTGTTTGATATTTCTTTT 1 3311 1055319 N/A N/A 324476 324495 TGATCTAAATTGTGTCTTTT 17 3312 1055325 N/A N/A 332359 332378 GTATTATAACAATTTGCATA 6 3313 1055330 N/A N/A 332365 332384 CAGGGAGTATTATAACAATT 2 3314 1055336 N/A N/A 334250 334269 TCATAGAAGCATTCTGTGTT 90 3315 1055342 N/A N/A 347821 347840 GTCATTATCTAGTTTCTGGA 2 3316 1055347 N/A N/A 347827 347846 CAAATGGTCATTATCTAGTT 10 3317 1055353 N/A N/A 355980 355999 ATCTGCTAGGCATGCGGGAT 27 3318 1055359 N/A N/A 396488 396507 TGATTTGTACACACCCAGCA 62 3319 1055365 N/A N/A 432459 432478 GCACTGATCCAATAAAACCC 93 3320

TABLE 45 Reduction of ATXN1 RNA by 5-10-5 MOE gapmers with mixed PO/PS linkages in A-431 Cells SEQ ID SEQ ID SEQ ID SEQ ID NO: 1 NO: 1 NO: 2 NO: 2 ATXN1 Compound Start Stop Start Stop (% SEQ Number Site Site Site Site Sequence (5′ to 3′) Control) ID NO 994605 N/A N/A 17726 17745 GTCACCTTTTCTATTTGCAC 2 138 994690 N/A N/A 179789 179808 GTTATATTTAATCATGTTCC 4 538 994734 N/A N/A 291014 291033 TCCTGGGTTTTTAGTTTTCC 2 232 1041358 N/A N/A 438300 438319 GAGAGTATAAAAATTATCTC 93 3073 1054947 107 126 2617 2636 CGGCTGCTGTTGCTCTGGCT 25 3321 1054952 113 132 2623 2642 GTCTTGCGGCTGCTGTTGCT 16 3322 1054964 245 264 10656 10675 GGTGACTTGATGCACGATGC 7 3323 1054969 252 271 10663 10682 CCACCCTGGTGACTTGATGC 13 3324 1054975 558 577 178168 178187 TAAGCTATCAGTTCCTTGCA 5 3325 1054980 564 583 178174 178193 GAACCATAAGCTATCAGTTC 24 3326 1054986 580 599 178190 178209 CTTTCATCACAATGGAGAAC 101 3327 1054992 589 608 178199 178218 TACCATGTGCTTTCATCACA 6 3328 1054997 596 615 N/A N/A AAAACTGTACCATGTGCTTT 4 3329 1055002 5493 5512 459746 459765 TTTGTTCAGTTTAGTTGCAG 17 3330 1055006 5500 5519 459753 459772 TCAGGTATTTGTTCAGTTTA 6 3331 1055011 5509 5528 459762 459781 AAAGAAAAGTCAGGTATTTG 42 3332 1055017 6032 6051 460285 460304 GTTGGTTTAGTGGATCCAGT 42 3333 1055021 6038 6057 460291 460310 CTTAGTGTTGGTTTAGTGGA 28 3334 1055026 9480 9499 463733 463752 AGATTGTTGTTATTGTATAG 20 3335 1055031 9487 9506 463740 463759 TTCTTAGAGATTGTTGTTAT 20 3336 1055037 9496 9515 463749 463768 TTATGGAAATTCTTAGAGAT 67 3337 1055042 10094 10113 464347 464366 GTAATGATCTGATATTAAAA 54 3338 1055047 10100 10119 464353 464372 TGGTGGGTAATGATCTGATA 14 3339 1055053 192 211 N/A N/A GTTTTTGTGAGGTAAAACTG 111 3340 1055058 199 218 9915 9934 TGTAGTAGTTTTTGTGAGGT 19 3341 1055061 208 227 9924 9943 CTTGGTGCTTGTAGTAGTTT 25 3342 1055067 N/A N/A 17724 17743 CACCTTTTCTATTTGCACTA 23 3343 1055073 N/A N/A 17732 17751 TCAAATGTCACCTTTTCTAT 52 3344 1055079 N/A N/A 49576 49595 ATAGCAAGTCCCCTGAAGCT 83 3345 1055085 N/A N/A 85513 85532 TGATATGCTATGCTCACAGA 25 3346 1055090 N/A N/A 85519 85538 TTAGTTTGATATGCTATGCT 36 3347 1055095 N/A N/A 99353 99372 CACAGAACACTTTTTCCAGA 41 3348 1055101 N/A N/A 144499 144518 ATCACACAGCAGCATGTTTA 72 3349 1055107 N/A N/A 179781 179800 TAATCATGTTCCCGATATTG 21 3350 1055117 N/A N/A 179797 179816 CTAACATAGTTATATTTAAT 121 3351 1055123 N/A N/A 184181 184200 GGTTTATATGTATACAATTC 3 3352 1055128 N/A N/A 184187 184206 TTCTCAGGTTTATATGTATA 5 3353 1055134 N/A N/A 203027 203046 TTCTTTGTTCATAGGAGAAC 91 3354 1055140 N/A N/A 203036 203055 GTTCCTTTCTTCTTTGTTCA 17 3355 1055145 N/A N/A 203043 203062 ACCTCTTGTTCCTTTCTTCT 10 3356 1055151 N/A N/A 203889 203908 GTTTAGATTTATCCTCAGGA 3 3357 1055156 N/A N/A 203895 203914 GGGTTTGTTTAGATTTATCC 19 3358 1055162 N/A N/A 210728 210747 TGTAATACTCCATTTTTCCT 15 3359 1055167 N/A N/A 210734 210753 CAAATGTGTAATACTCCATT 16 3360 1055173 N/A N/A 212025 212044 TTAGTCATTTCTCTCTGGCT 50 3361 1055178 N/A N/A 212032 212051 GTCTATGTTAGTCATTTCTC 13 3362 1055184 N/A N/A 212041 212060 AAAAATCAAGTCTATGTTAG 118 3363 1055190 N/A N/A 217281 217300 ATGTTTAAGGTATTTTCATG 41 3364 1055195 N/A N/A 217287 217306 ACAGTTATGTTTAAGGTATT 39 3365 1055201 N/A N/A 226199 226218 AAAACAGACTTCGATTTGGA 70 3366 1055207 N/A N/A 226994 227013 GTTATTTACTCATTCTACCT 42 3367 1055212 N/A N/A 227000 227019 AACTTGGTTATTTACTCATT 25 3368 1055218 N/A N/A 233991 234010 AAGTTGGAGAAGTCACCAGC 103 3369 1055224 N/A N/A 251500 251519 GCATACTTAGCTTTTCAAAT 6 3370 1055229 N/A N/A 251506 251525 GTGTCAGCATACTTAGCTTT 27 3371 1055235 N/A N/A 254560 254579 TCTTGGAGGTGACATTTGTG 55 3372 1055241 N/A N/A 284225 284244 GTTTTTCTGTACAAAGTTCA 2 3373 1055246 N/A N/A 284232 284251 TGTTTGGGTTTTTCTGTACA 1 3374 1055252 N/A N/A 284241 284260 CTTTAGTTTTGTTTGGGTTT 2 3375 1055258 N/A N/A 284339 284358 TCAACTAGTTCTTATCACTA 4 3376 1055263 N/A N/A 284345 284364 ACAATGTCAACTAGTTCTTA 2 3377 1055269 N/A N/A 291006 291025 TTTTAGTTTTCCTTCTTGTC 5 3378 1055280 N/A N/A 291022 291041 AGATTAGGTCCTGGGTTTTT 2 3379 1055286 N/A N/A 297002 297021 TGCATTAAATGACTGTGGTG 4 3380 1055291 N/A N/A 297008 297027 AGTGTTTGCATTAAATGACT 5 3381 1055297 N/A N/A 306732 306751 CCACTAAATCTGACCTTCCT 37 3382 1055303 N/A N/A 306746 306765 TCCATTGGTAAGGGCCACTA 2 3383 1055309 N/A N/A 318483 318502 TTTGATATTTCTTTTTTTTT 96 3384 1055314 N/A N/A 318489 318508 AATGTGTTTGATATTTCTTT 1 3385 1055320 N/A N/A 326832 326851 CAGTTTTGAGATGGTTTGAA 3 3386 1055326 N/A N/A 332360 332379 AGTATTATAACAATTTGCAT 22 3387 1055331 N/A N/A 332366 332385 CCAGGGAGTATTATAACAAT 2 3388 1055337 N/A N/A 347813 347832 CTAGTTTCTGGAAAGTAATG 36 3389 1055343 N/A N/A 347822 347841 GGTCATTATCTAGTTTCTGG 1 3390 1055348 N/A N/A 347829 347848 AACAAATGGTCATTATCTAG 9 3391 1055354 N/A N/A 358326 358345 CCAAATTCCTGGTTGCTGTG 4 3392 1055360 N/A N/A 397561 397580 AGGGCCTCTTGGATTTTGTT 130 3393

TABLE 46 Reduction of ATXN1 RNA by 5-10-5 MOE gapmers with mixed PO/PS linkages in A-431 Cells SEQ ID SEQ ID SEQ ID SEQ ID NO: 1 NO: 1 NO: 2 NO: 2 ATXN1 Compound Start Stop Start Stop (% SEQ Number Site Site Site Site Sequence (5′ to 3′) Control) ID NO 994314 246 265 10657 10676 TGGTGACTTGATGCACGATG 12 491 994329 590 609 178200 178219 GTACCATGTGCTTTCATCAC 5 415 994465 6033 6052 460286 460305 TGTTGGTTTAGTGGATCCAG 21 432 994467 6040 6059 460293 460312 ATCTTAGTGTTGGTTTAGTG 20 588 994605 N/A N/A 17726 17745 GTCACCTTTTCTATTTGCAC 4 138 994700 N/A N/A 203037 203056 TGTTCCTTTCTTCTTTGTTC 10 72 994761 N/A N/A 347823 347842 TGGTCATTATCTAGTTTCTG 2 469 1054948 108 127 2618 2637 GCGGCTGCTGTTGCTCTGGC 57 3394 1054953 114 133 2624 2643 TGTCTTGCGGCTGCTGTTGC 16 3395 1054970 254 273 10665 10684 GACCACCCTGGTGACTTGAT 9 3396 1054976 559 578 178169 178188 ATAAGCTATCAGTTCCTTGC 11 3397 1054981 565 584 178175 178194 AGAACCATAAGCTATCAGTT 7 3398 1054987 582 601 178192 178211 TGCTTTCATCACAATGGAGA 62 3399 1054998 598 617 N/A N/A GGAAAACTGTACCATGTGCT 4 3400 1055003 5495 5514 459748 459767 TATTTGTTCAGTTTAGTTGC 9 3401 1055007 5501 5520 459754 459773 GTCAGGTATTTGTTCAGTTT 9 3402 1055012 6024 6043 460277 460296 AGTGGATCCAGTCAATTCAA 34 3403 1055027 9482 9501 463735 463754 AGAGATTGTTGTTATTGTAT 16 3404 1055032 9488 9507 463741 463760 ATTCTTAGAGATTGTTGTTA 21 3405 1055038 10086 10105 464339 464358 CTGATATTAAAACATCCAGT 21 3406 1055043 10095 10114 464348 464367 GGTAATGATCTGATATTAAA 15 3407 1055048 10102 10121 464355 464374 TATGGTGGGTAATGATCTGA 16 3408 1055054 194 213 9910 9929 TAGTTTTTGTGAGGTAAAAC 83 3409 1055059 200 219 9916 9935 TTGTAGTAGTTTTTGTGAGG 28 3410 1055062 N/A N/A 17716 17735 CTATTTGCACTAGCTGCCTA 75 3411 1055068 N/A N/A 17725 17744 TCACCTTTTCTATTTGCACT 10 3412 1055074 N/A N/A 17734 17753 TCTCAAATGTCACCTTTTCT 44 3413 1055080 N/A N/A 54036 54055 AACCATATGACATCTCAACA 33 3414 1055086 N/A N/A 85514 85533 TTGATATGCTATGCTCACAG 18 3415 1055091 N/A N/A 85520 85539 GTTAGTTTGATATGCTATGC 36 3416 1055096 N/A N/A 103883 103902 CAACTGAAAATTCTACACAC 110 3417 1055102 N/A N/A 147181 147200 CAGTAGTCTCCCCATAGCCA 76 3418 1055108 N/A N/A 179783 179802 TTTAATCATGTTCCCGATAT 57 3419 1055113 N/A N/A 179790 179809 AGTTATATTTAATCATGTTC 17 3420 1055118 N/A N/A 179799 179818 CACTAACATAGTTATATTTA 72 3421 1055124 N/A N/A 184182 184201 AGGTTTATATGTATACAATT 13 3422 1055129 N/A N/A 184188 184207 GTTCTCAGGTTTATATGTAT 5 3423 1055135 N/A N/A 203029 203048 TCTTCTTTGTTCATAGGAGA 147 3424 1055146 N/A N/A 203045 203064 CAACCTCTTGTTCCTTTCTT 52 3425 1055152 N/A N/A 203890 203909 TGTTTAGATTTATCCTCAGG 5 3426 1055157 N/A N/A 210720 210739 TCCATTTTTCCTTCTAGATT 19 3427 1055163 N/A N/A 210729 210748 GTGTAATACTCCATTTTTCC 5 3428 1055168 N/A N/A 210736 210755 TACAAATGTGTAATACTCCA 6 3429 1055174 N/A N/A 212027 212046 TGTTAGTCATTTCTCTCTGG 23 3430 1055179 N/A N/A 212033 212052 AGTCTATGTTAGTCATTTCT 24 3431 1055185 N/A N/A 213048 213067 GATGATAAATTAAGGCAGAG 22 3432 1055191 N/A N/A 217282 217301 TATGTTTAAGGTATTTTCAT 47 3433 1055196 N/A N/A 217288 217307 AACAGTTATGTTTAAGGTAT 43 3434 1055202 N/A N/A 226986 227005 CTCATTCTACCTTCAACTCT 94 3435 1055208 N/A N/A 226995 227014 GGTTATTTACTCATTCTACC 14 3436 1055213 N/A N/A 227002 227021 TAAACTTGGTTATTTACTCA 79 3437 1055219 N/A N/A 236034 236053 GAGTGAGCATTAGATGGTCA 56 3438 1055225 N/A N/A 251501 251520 AGCATACTTAGCTTTTCAAA 10 3439 1055230 N/A N/A 251507 251526 AGTGTCAGCATACTTAGCTT 16 3440 1055236 N/A N/A 257663 257682 AGGGAAATGGTCATTTTCTA 87 3441 1055242 N/A N/A 284227 284246 GGGTTTTTCTGTACAAAGTT 4 3442 1055247 N/A N/A 284233 284252 TTGTTTGGGTTTTTCTGTAC 3 3443 1055253 N/A N/A 284331 284350 TTCTTATCACTATTCAGTCA 3 3444 1055259 N/A N/A 284340 284359 GTCAACTAGTTCTTATCACT 2 3445 1055264 N/A N/A 284347 284366 AAACAATGTCAACTAGTTCT 12 3446 1055270 N/A N/A 291008 291027 GTTTTTAGTTTTCCTTCTTG 3 3447 1055275 N/A N/A 291015 291034 GTCCTGGGTTTTTAGTTTTC 2 3448 1055281 N/A N/A 291024 291043 GAAGATTAGGTCCTGGGTTT 5 3449 1055287 N/A N/A 297003 297022 TTGCATTAAATGACTGTGGT 2 3450 1055292 N/A N/A 297009 297028 CAGTGTTTGCATTAAATGAC 3 3451 1055298 N/A N/A 306734 306753 GGCCACTAAATCTGACCTTC 54 3452 1055304 N/A N/A 306748 306767 AATCCATTGGTAAGGGCCAC 4 3453 1055310 N/A N/A 318484 318503 GTTTGATATTTCTTTTTTTT 2 3454 1055315 N/A N/A 318491 318510 CAAATGTGTTTGATATTTCT 3 3455 1055321 N/A N/A 332352 332371 AACAATTTGCATAGTCTCTC 3 3456 1055327 N/A N/A 332361 332380 GAGTATTATAACAATTTGCA 3 3457 1055332 N/A N/A 332368 332387 TTCCAGGGAGTATTATAACA 2 3458 1055338 N/A N/A 347815 347834 ATCTAGTTTCTGGAAAGTAA 22 3459 1055349 N/A N/A 347831 347850 ATAACAAATGGTCATTATCT 43 3460 1055355 N/A N/A 365965 365984 AATCCAAATCTTGTATTCTT 9 3461 1055361 N/A N/A 399995 400014 TCTAGAAATGATTTTGATTA 107 3462 1055366 N/A N/A 439847 439866 TGGGCATTTAAGAAATGCTC 140 3463

TABLE 47 Reduction of ATXN1 RNA by 5-10-5 MOE gapmers with mixed PO/PS linkages in A-431 Cells SEQ ID SEQ ID SEQ ID SEQ ID NO: 1 NO: 1 NO: 2 NO: 2 ATXN1 Compound Start Stop Start Stop (% SEQ Number Site Site Site Site Sequence (5′ to 3′) Control) ID NO 994448 5496 5515 459749 459768 GTATTTGTTCAGTTTAGTTG 9 352 994466 6034 6053 460287 460306 GTGTTGGTTTAGTGGATCCA 21 510 994571 10096 10115 464349 464368 GGGTAATGATCTGATATTAA 10 601 994598 201 220 9917 9936 CTTGTAGTAGTTTTTGTGAG 42 215 994605 N/A N/A 17726 17745 GTCACCTTTTCTATTTGCAC 3 138 994702 N/A N/A 210730 210749 TGTGTAATACTCCATTTTTC 8 228 994713 N/A N/A 226996 227015 TGGTTATTTACTCATTCTAC 10 463 994732 N/A N/A 284341 284360 TGTCAACTAGTTCTTATCAC 3 76 994743 N/A N/A 318485 318504 TGTTTGATATTTCTTTTTTT 3 311 994756 N/A N/A 332362 332381 GGAGTATTATAACAATTTGC 1 79 1040299 5502 5521 459755 459774 AGTCAGGTATTTGTTCAGTT 6 2809 1040631 10088 10107 464341 464360 ATCTGATATTAAAACATCCA 18 1280 1054949 109 128 2619 2638 TGCGGCTGCTGTTGCTCTGG 22 3464 1054954 115 134 2625 2644 ATGTCTTGCGGCTGCTGTTG 10 3465 1054965 247 266 10658 10677 CTGGTGACTTGATGCACGAT 21 3466 1054971 256 275 10667 10686 TGGACCACCCTGGTGACTTG 17 3467 1054977 560 579 178170 178189 CATAAGCTATCAGTTCCTTG 5 3468 1054982 566 585 178176 178195 GAGAACCATAAGCTATCAGT 11 3469 1054988 584 603 178194 178213 TGTGCTTTCATCACAATGGA 56 3470 1054993 591 610 178201 178220 TGTACCATGTGCTTTCATCA 3 3471 1054999 600 619 N/A N/A TTGGAAAACTGTACCATGTG 8 3472 1055013 6026 6045 460279 460298 TTAGTGGATCCAGTCAATTC 31 3473 1055022 6042 6061 460295 460314 CCATCTTAGTGTTGGTTTAG 23 3474 1055028 9483 9502 463736 463755 TAGAGATTGTTGTTATTGTA 14 3475 1055033 9489 9508 463742 463761 AATTCTTAGAGATTGTTGTT 19 3476 1055049 10104 10123 464357 464376 CATATGGTGGGTAATGATCT 62 3477 1055055 195 214 9911 9930 GTAGTTTTTGTGAGGTAAAA 8 3478 1055063 N/A N/A 17718 17737 TTCTATTTGCACTAGCTGCC 78 3479 1055069 N/A N/A 17727 17746 TGTCACCTTTTCTATTTGCA 2 3480 1055075 N/A N/A 17736 17755 CCTCTCAAATGTCACCTTTT 85 3481 1055081 N/A N/A 85506 85525 CTATGCTCACAGAGAACCTG 98 3482 1055087 N/A N/A 85515 85534 TTTGATATGCTATGCTCACA 13 3483 1055092 N/A N/A 85522 85541 CAGTTAGTTTGATATGCTAT 25 3484 1055097 N/A N/A 103952 103971 TGTGATTTATCGCTGACCTT 53 3485 1055103 N/A N/A 148568 148587 GAATGGTTCTCTTTTACGGG 8 3486 1055109 N/A N/A 179785 179804 TATTTAATCATGTTCCCGAT 19 3487 1055114 N/A N/A 179791 179810 TAGTTATATTTAATCATGTT 63 3488 1055119 N/A N/A 184174 184193 ATGTATACAATTCTGACAGT 49 3489 1055125 N/A N/A 184183 184202 CAGGTTTATATGTATACAAT 5 3490 1055130 N/A N/A 184190 184209 ATGTTCTCAGGTTTATATGT 5 3491 1055136 N/A N/A 203031 203050 TTTCTTCTTTGTTCATAGGA 71 3492 1055141 N/A N/A 203038 203057 TTGTTCCTTTCTTCTTTGTT 46 3493 1055147 N/A N/A 203047 203066 AACAACCTCTTGTTCCTTTC 13 3494 1055153 N/A N/A 203891 203910 TTGTTTAGATTTATCCTCAG 6 3495 1055158 N/A N/A 210722 210741 ACTCCATTTTTCCTTCTAGA 6 3496 1055169 N/A N/A 210738 210757 ATTACAAATGTGTAATACTC 62 3497 1055175 N/A N/A 212028 212047 ATGTTAGTCATTTCTCTCTG 20 3498 1055180 N/A N/A 212034 212053 AAGTCTATGTTAGTCATTTC 31 3499 1055186 N/A N/A 217274 217293 AGGTATTTTCATGGAGTTTC 3 3500 1055192 N/A N/A 217283 217302 TTATGTTTAAGGTATTTTCA 60 3501 1055197 N/A N/A 217290 217309 GTAACAGTTATGTTTAAGGT 8 3502 1055203 N/A N/A 226988 227007 TACTCATTCTACCTTCAACT 72 3503 1055214 N/A N/A 227004 227023 CATAAACTTGGTTATTTACT 65 3504 1055220 N/A N/A 248565 248584 CCACTACCACCCCCAAACCA 53 3505 1055226 N/A N/A 251502 251521 CAGCATACTTAGCTTTTCAA 16 3506 1055231 N/A N/A 251508 251527 CAGTGTCAGCATACTTAGCT 20 3507 1055237 N/A N/A 259737 259756 CATGTATTGCTAGGAGCCAG 46 3508 1055243 N/A N/A 284228 284247 TGGGTTTTTCTGTACAAAGT 2 3509 1055248 N/A N/A 284234 284253 TTTGTTTGGGTTTTTCTGTA 2 3510 1055254 N/A N/A 284333 284352 AGTTCTTATCACTATTCAGT 2 3511 1055265 N/A N/A 284349 284368 CTAAACAATGTCAACTAGTT 61 3512 1055271 N/A N/A 291010 291029 GGGTTTTTAGTTTTCCTTCT 2 3513 1055276 N/A N/A 291016 291035 GGTCCTGGGTTTTTAGTTTT 3 3514 1055282 N/A N/A 296995 297014 AATGACTGTGGTGCAGCCTC 27 3515 1055288 N/A N/A 297004 297023 TTTGCATTAAATGACTGTGG 2 3516 1055293 N/A N/A 297011 297030 GCCAGTGTTTGCATTAAATG 2 3517 1055299 N/A N/A 306736 306755 AGGGCCACTAAATCTGACCT 118 3518 1055305 N/A N/A 306750 306769 AGAATCCATTGGTAAGGGCC 6 3519 1055316 N/A N/A 318493 318512 TTCAAATGTGTTTGATATTT 12 3520 1055322 N/A N/A 332354 332373 ATAACAATTTGCATAGTCTC 4 3521 1055333 N/A N/A 332370 332389 TTTTCCAGGGAGTATTATAA 21 3522 1055339 N/A N/A 347817 347836 TTATCTAGTTTCTGGAAAGT 39 3523 1055344 N/A N/A 347824 347843 ATGGTCATTATCTAGTTTCT 2 3524 1055350 N/A N/A 347833 347852 TGATAACAAATGGTCATTAT 32 3525 1055356 N/A N/A 372672 372691 CATCAAAATTGTGCACAATT 81 3526 1055362 N/A N/A 402059 402078 TGAAAACATGTTGTGTGATT 57 3527 1055367 N/A N/A 453507 453526 TTGTTGGATTCTTTTTTTCT 27 3528

TABLE 48 Reduction of ATXN1 RNA by 5-10-5 MOE gapmers with mixed PO/PS linkages in A-431 Cells SEQ SEQ ID ID NO: NO: ATXN1  Com- 3 3 (% SEQ pound Start Stop Con- ID Number Site Site Sequence (5′to 3′) trol) NO 1054961 193 212 GACTTGATGCACGATGCTCT 8 3529 1054958 187 206 ATGCACGATGCTCTGTAAAG 51 3530 1054959 189 208 TGATGCACGATGCTCTGTAA 42 3531 1054960 191 210 CTTGATGCACGATGCTCTGT 48 3532

Example 3: Effect of Modified Oligonucleotides on Human ATXN1 RNA In Vitro, Multiple Doses

Modified oligonucleotides selected from the examples above were tested at various doses in A-431 cells. Cultured A-431 cells at a density of 10,000 cells per well were treated using free uptake with various concentrations of modified oligonucleotide as specified in the tables below. After a treatment period of approximately 48 hours, total RNA was isolated from the cells and ATXN1 RNA levels were measured by quantitative real-time RTPCR. Human ATXN1 primer probe set RTS37573 was used to measure RNA levels as described above. ATXN1 levels were adjusted according to total RNA content, as measured by RIBOGREEN®. Results are presented in the tables below as percent reduction of the amount of ATXN1 RNA, relative to untreated control. Where possible, the half maximal inhibitory concentration (IC₅₀) of each modified oligonucleotide was calculated using a linear regression on a log/linear plot of the data in excel.

TABLE 49 Dose-dependent percent reduction of human ATXN1 RNA in A-431 cells by modified oligonucleotides % Control Compound 2000 8000 IC50 No. 125 nM 500 nM nM nM (μM) 994310 60 32 19 12 0.2 994316 36 15 9 9 <0.1 994318 46 12 9 7 <0.1 994319 31 13 8 7 <0.1 994392 50 26 13 10 <0.1 994421 16 8 8 10 <0.1 994492 48 25 15 15 <0.1 994542 55 36 25 22 0.1 994612 22 11 9 9 <0.1 994613 30 23 15 14 <0.1 994623 59 50 40 35 0.5 994628 21 9 7 9 <0.1 994631 42 25 12 10 <0.1 994645 90 78 68 56 >8.0 994646 64 39 28 21 0.3 994652 24 11 9 9 <0.1 994653 35 21 13 11 <0.1 994812 31 13 9 8 <0.1

TABLE 50 Dose-dependent percent reduction of human ATXN1 RNA in A-431 cells by modified oligonucleotides % Control Compound 2000 8000 IC50 No. 125 nM 500 nM nM nM (μM) 994315 7 6 6 7 <0.1 994320 11 7 4 5 <0.1 994321 42 25 13 6 <0.1 994395 41 27 21 12 <0.1 994609 18 9 8 7 <0.1 994610 94 95 79 63 >8.0 994612 23 11 9 10 <0.1 994616 70 51 40 27 0.7 994618 60 25 16 14 0.1 994619 53 32 18 10 <0.1 994642 52 26 16 11 <0.1 994643 56 35 23 17 0.2 994649 39 23 19 18 <0.1 994651 21 9 7 6 <0.1 994656 62 35 20 14 0.2 994696 34 17 12 9 <0.1 994698 82 58 51 36 1.9 994770 46 23 12 11 <0.1 994913 48 30 18 12 <0.1

TABLE 51 Dose-dependent percent reduction of human ATXN1 RNA by modified oligonucleotides % Control Compound 2000 8000 IC50 No. 125 nM 500 nM nM nM (μM) 994328 115 120 134 116 >8.0 994597 57 24 11 10 <0.1 994599 55 36 30 22 0.1 994612 28 12 8 12 <0.1 994630 68 43 26 15 0.4 994638 76 40 22 15 0.4 994693 78 55 35 17 0.8 994700 12 5 4 4 <0.1 994701 63 36 19 16 0.2 994702 50 27 16 12 <0.1 994703 66 43 29 16 0.4 994717 11 8 9 6 <0.1 994732 21 11 9 9 <0.1 994734 9 4 2 2 <0.1 994735 49 21 15 14 <0.1 994740 67 37 20 15 0.3 994743 23 11 9 11 <0.1 994756 39 21 13 12 <0.1 994918 63 41 24 15 0.3

TABLE 52 Dose-dependent percent reduction of human ATXN1 RNA by modified oligonucleotides % Control Compound 2000 8000 IC50 No. 125 nM 500 nM nM nM (μM) 994313 63 31 15 9 0.2 994314 41 19 10 15 <0.1 994329 18 7 5 5 <0.1 994346 17 8 6 8 <0.1 994449 28 9 8 10 <0.1 994466 103 104 79 79 >8.0 994474 36 14 13 11 <0.1 994497 16 9 9 10 <0.1 994561 34 17 12 10 <0.1 994571 95 77 76 73 >8.0 994612 26 12 10 9 <0.1 994690 87 60 42 40 1.9 994697 23 10 6 5 <0.1 994706 12 7 5 5 <0.1 994713 79 61 24 11 0.7 994731 65 31 18 16 0.2 994761 57 25 14 14 <0.1 994835 75 36 21 19 0.4 994848 61 33 22 16 0.2

Example 4: Design of Modified Oligonucleotides Complementary to a Human ATXN1 Nucleic Acid

Modified oligonucleotides were designed and synthesized as indicated in the tables below.

The compounds in table 53 are 5-10-5 MOE gapmers with mixed internucleoside linkages. The gapmers are 20 nucleosides in length, wherein the central gap segment consists of ten 2′-β-D-deoxynucleosides, the 5′ wing segment consists of five 2′-MOE nucleosides, and the 3′ wing segment consists of five 2′-MOE nucleosides. The sugar motif of the gapmers is (from 5′ to 3′): eeeeeddddddddddeeeee; wherein ‘d’ represents a 2′-β-D-deoxyribosyl sugar moiety, and ‘e’ represents a 2′-MOE sugar moiety. The gapmers have an internucleoside linkage motif of (from 5′ to 3′): sooosssssssssssooss; wherein “s” represents a phosphorothioate internucleoside linkage and “o” represents a phosphodiester internucleoside linkage. All cytosine residues are 5-methylcytosines.

TABLE 53 5-10-5 MOE gapmers with mixed PO/PS internucleoside linkages complementary to human ATXN1 SEQ ID SEQ ID SEQ ID SEQ ID Compound No: 1 No: 1 No: 2 Start No: 2 Stop SEQ Number SEQUENCE Start Site Stop Site Site Site ID No. 1342029 TGATTGTGTTCCATTGTAAA 7023 7042 461276 461295 3533 1342030 GAGTTGTCCATAGTCATGAA 4432 4451 458685 458704 3534 1342031 CGAGTTGTCCATAGTCATGA 4433 4452 458686 458705 3535 1342033 TGCACTTTTGTTTCTACAGC N/A N/A 441087 441106 3536 1342034 AGGCCTTGCACTTTTGTTTC N/A N/A 441093 441112 3537 1342035 AAGTGGCACCCGAGTTGTCC 4443 4462 458696 458715 3538 1342036 GCCTTGCACTTTTGTTTCTA N/A N/A 441091 441110 3539 1342037 GATTGTGTTCCATTGTAAAC 7022 7041 461275 461294 3540 1342039 GTGGATCCAGTCAATTCAAT 6023 6042 460276 460295 3541 1342040 AATAGCAGCTATTTCATGAC N/A N/A 439446 439465 3542 1342044 TGGATCCAGTCAATTCAATA 6022 6041 460275 460294 3543 1342045 TCAATTCAATACTCGAAGTA 6013 6032 460266 460285 3544 1342046 GGATCCAGTCAATTCAATAC 6021 6040 460274 460293 3545 1342050 CAATGACTCTTCACTCATGT N/A N/A 440235 440254 3546 1342051 ACTATTTTCAACTCAAGCTG N/A N/A 439428 439447 3547 1342052 GACTCTTCACTCATGTTTAT N/A N/A 440231 440250 3548 1342053 GGTACTGGCTCATCAGTTGT N/A N/A 444368 444387 3549 1342054 AATGACTCTTCACTCATGTT N/A N/A 440234 440253 3550 1342055 AGCAATGACTCTTCACTCAT N/A N/A 440237 440256 3551 1342057 AAGCAATGACTCTTCACTCA N/A N/A 440238 440257 3552 1342060 AACCAATCTATCACACCAAT N/A N/A 444348 444367 3553 1342063 AGCCATCCAAGTAAGAATAT 5475 5494 459728 459747 3554 1342065 ACCAATCTATCACACCAATG N/A N/A 444347 444366 3555 1342066 CAATCTATCACACCAATGCA N/A N/A 444345 444364 3556 1342068 CAGCCATCCAAGTAAGAATA 5476 5495 459729 459748 3557 1342069 TATTGTCACATACTAGTTCA 4755 4774 459008 459027 3558 1342070 CTGACTAATTTCTTGGTGAT 7039 7058 461292 461311 3559 1342074 GTGGTCATTTATTGTCACAT 4764 4783 459017 459036 3560 1342075 GTCACATACTAGTTCATAAT 4751 4770 459004 459023 3561 1342076 TTATTGTCACATACTAGTTC 4756 4775 459009 459028 3562 1342032 CCCGAGTTGTCCATAGTCAT 4435 4454 458688 458707 3563 1342038 CATTGTAAACGCAAAAGGCC 7012 7031 461265 461284 3564 1342041 CAGTCAATTCAATACTCGAA 6016 6035 460269 460288 3565 1342042 GTCCATAGTCATGAACTATA 4427 4446 458680 458699 3566 1342043 ATAGCAGCTATTTCATGACT N/A N/A 439445 439464 3567 1342047 GTCAATTCAATACTCGAAGT 6014 6033 460267 460286 3568 1342048 GATCCAGTCAATTCAATACT 6020 6039 460273 460292 3569 1342049 TAACCAATCTATCACACCAA N/A N/A 444349 444368 3570 1342056 ATGACTCTTCACTCATGTTT N/A N/A 440233 440252 3571 1342058 GACTATTTTCAACTCAAGCT N/A N/A 439429 439448 3572 1342059 CTTGGTGGTCATTTATTGTC 4768 4787 459021 459040 3573 1342061 GGTGGTCATTTATTGTCACA 4765 4784 459018 459037 3574 1342062 TAGTTGCAGCCATCCAAGTA 5482 5501 459735 459754 3575 1342064 TGGTGGTCATTTATTGTCAC 4766 4785 459019 459038 3576 1342067 GTTCAGTTTAGTTGCAGCCA 5490 5509 459743 459762 3577 1342071 CATACTAGTTCATAATTCAC 4747 4766 459000 459019 3578 1342072 TCGCCCTGACTAATTTCTTG 7044 7063 461297 461316 3579 1342073 CCCTGACTAATTTCTTGGTG 7041 7060 461294 461313 3580 1342077 GCCCTGACTAATTTCTTGGT 7042 7061 461295 461314 3581

The compounds in table 54 are 5-10-5 MOE gapmers with mixed internucleoside linkages. The gapmers are 20 nucleosides in length, wherein the central gap segment consists of ten 2′-β-D-deoxynucleosides, the 5′ wing segment consists of five 2′-MOE nucleosides, and the 3′ wing segment consists of five 2′-MOE nucleosides. The sugar motif of the gapmers is (from 5′ to 3′): eeeeeddddddddddeeeee; wherein ‘d’ represents a 2′-β-D-deoxyribosyl sugar moiety, and ‘e’ represents a 2′-MOE sugar moiety. The gapmers have an internucleoside linkage motif of (from 5′ to 3′): sssosssssssssssosss; wherein “s” represents a phosphorothioate internucleoside linkage and “o” represents a phosphodiester internucleoside linkage. All cytosine residues are 5-methylcytosines.

TABLE 54 5-10-5 MOE gapmers with mixed PO/PS internucleoside linkages complementary to human ATXN1 SEQ ID SEQ ID SEQ ID SEQ ID No: 1 No: 1 No: 2 No: 2 Compound Start Stop Start Stop SEQ Number SEQUENCE Site Site Site Site ID No. 1364280 ACCCGAGTTGTCCATAGTCA 4436 4455 458689 458708 582 1364281 CCACGCTTTTATTTTCTGAT N/A N/A 439093 439112 2074 1364282 GCCTTTATAACTTTTCTTTC N/A N/A 446680 446699 2552 1364283 GGTCATTTATTGTCACATAC 4762 4781 459015 459034 194 1364285 ATTTTCTTTTTTCTGTGCCT N/A N/A 452653 452672 488 1367569 TTCCTCTTACCATCAAAGGC 5906 5925 460159 460178 2502 1367572 CGTGGGTGTTCGCTCTCTCC 4256 4275 458509 458528 3582 1367573 GCGTGGGTGTTCGCTCTCTC 4257 4276 458510 458529 3583 1367575 CTCTTACCATCAAAGGCTAA 5903 5922 460156 460175 3584 1367576 CCTCTTACCATCAAAGGCTA 5904 5923 460157 460176 2425 1367577 TCCTCTTACCATCAAAGGCT 5905 5924 460158 460177 431 1367580 CAGCCCGTATTCCTCTTACC 5915 5934 460168 460187 509 1367581 TGTGGCAGCCCGTATTCCTC 5920 5939 460173 460192 3585 1367586 GGGTGTTCGCTCTCTCCCTC 4253 4272 458506 458525 3586 1367588 GTGGGTGTTCGCTCTCTCCC 4255 4274 458508 458527 3587 1367589 CCGTATTCCTCTTACCATCA 5911 5930 460164 460183 3588 1367590 GTATTCCTCTTACCATCAAA 5909 5928 460162 460181 3589 1367591 CCCGTATTCCTCTTACCATC 5912 5931 460165 460184 3590 1394153 CCCGAGTTGTCCATAGTCAT 4435 4454 458688 458707 3563 1394154 GCACCCGAGTTGTCCATAGT 4438 4457 458691 458710 3605 1394155 CACCCGAGTTGTCCATAGTC 4437 4456 458690 458709 3593 1394156 GTCAGGTATTTGTTCAGTTT 5501 5520 459754 459773 3402 1394157 TGTTCAGTTTAGTTGCAGCC 5491 5510 459744 459763 274 1394158 TTGTTCAGTTTAGTTGCAGC 5492 5511 459745 459764 3655 1394159 GTTCAGTTTAGTTGCAGCCA 5490 5509 459743 459762 3577 1394160 TCAGGTATTTGTTCAGTTTA 5500 5519 459753 459772 3331 1394161 GCCCGTATTCCTCTTACCAT 5913 5932 460166 460185 2579 1394507 GGTGGTCATTTATTGTCACA 4765 4784 459018 459037 3574 1394508 GTGATTGTGTTCCATTGTAA 7024 7043 461277 461296 201 1394510 CCTTGCACTTTTGTTTCTAC N/A N/A 441090 441109 321 1394511 GTGGTCATTTATTGTCACAT 4764 4783 459017 459036 3560 1394512 ATGTGTTCTTAAATTCTCTA 8210 8229 462463 462482 1583 1394513 GCACGGTATTAGTGTCTTCA 7892 7911 462145 462164 126 1394514 GCTTCTCAAATCAGGTGTAC 8481 8500 462734 462753 1045 1394515 TGATTGTGTTCCATTGTAAA 7023 7042 461276 461295 3533 1394516 GTTTGTTGGTTTCTTATTAA 7083 7102 461336 461355 46 1394517 CTGTATATTTATTACTTGAT 8228 8247 462481 462500 1891 1394518 TGGTCATTTATTGTCACATA 4763 4782 459016 459035 3038

The compounds in table 55 are 6-10-4 MOE gapmers with mixed internucleoside linkages. The gapmers are 20 nucleosides in length, wherein the central gap segment consists of ten 2′-β-D-deoxynucleosides, the 5′ wing segment consists of six 2′-MOE nucleosides, and the 3′ wing segment consists of four 2′-MOE nucleosides. The sugar motif of the gapmers is (from 5′ to 3′): eeeeeeddddddddddeeee; wherein ‘d’ represents a 2′-β-D-deoxyribosyl sugar moiety, and ‘e’ represents a 2′-MOE sugar moiety. The gapmers have an internucleoside linkage motif of (from 5′ to 3′): sooooossssssssssoss; wherein “s” represents a phosphorothioate internucleoside linkage and “o” represents a phosphodiester internucleoside linkage. All cytosine residues are 5-methylcytosines.

TABLE 55 6-10-4 MOE gapmers with mixed PO/PS internucleoside linkages complementary to human ATXN1 SEQ ID SEQ ID SEQ ID SEQ ID No: 1 No: 1 No: 2 No: 2 Compound Start Stop Start Stop SEQ ID Number SEQUENCE Site Site Site Site No. 1371806 GTTCGCTCTCTCCCTCTCCC 4249 4268 458502 458521 114 1371807 TTTTCTTTTCGCCCTGACTA 7052 7071 461305 461324 3591 1371808 TCATTTATTGTCACATACTA 4760 4779 459013 459032 3592 1371809 CACCCGAGTTGTCCATAGTC 4437 4456 458690 458709 3593 1371810 GTCATTTATTGTCACATACT 4761 4780 459014 459033 3594 1371811 TTTTTTCTTTTCGCCCTGAC 7054 7073 461307 461326 3595 1371812 GTTGTCCATAGTCATGAACT 4430 4449 458683 458702 3596 1371813 TAATTCACATTCATCCCTTT 4735 4754 458988 459007 3597 1371814 CCCTGACTAATTTCTTGGTG 7041 7060 461294 461313 3580 1371815 ATAATTCACATTCATCCCTT 4736 4755 458989 459008 2268 1371816 TGGTCATTTATTGTCACATA 4763 4782 459016 459035 3038 1371817 TTGTCCATAGTCATGAACTA 4429 4448 458682 458701 2421 1371818 AGTTGCAGCCATCCAAGTAA 5481 5500 459734 459753 2655 1371819 GTTCATAATTCACATTCATC 4740 4759 458993 459012 2499 1371820 GCCCCCAAACCCATTTTCTT N/A N/A 452665 452684 1026 1371821 CAGCCATCCAAGTAAGAATA 5476 5495 459729 459748 3557 1371822 TTCATAATTCACATTCATCC 4739 4758 458992 459011 2422 1371823 GAGAACAAAGTCTATGTGGC 5934 5953 460187 460206 2733 1371824 CCCGAGTTGTCCATAGTCAT 4435 4454 458688 458707 3563 1371825 AGCCCGTATTCCTCTTACCA 5914 5933 460167 460186 2656 1371826 TCCTAACACTGCACAGAAAC 4279 4298 458532 458551 3598 1371827 TCAGGTATTTGTTCAGTTTA 5500 5519 459753 459772 3331 1371828 TCCATAGTCATGAACTATAA 4426 4445 458679 458698 3599 1371829 GTCAGGTATTTGTTCAGTTT 5501 5520 459754 459773 3402 1371830 GTGATTGTGTTCCATTGTAA 7024 7043 461277 461296 201 1371831 CCATAGTCATGAACTATAAA 4425 4444 458678 458697 3600 1371832 TTTTTCTGTGCCTCCTGACC N/A N/A 452646 452665 795 1371833 TGATTGTGTTCCATTGTAAA 7023 7042 461276 461295 3533 1371834 CCTGACTAATTTCTTGGTGA 7040 7059 461293 461312 2350 1371835 CATAGTCATGAACTATAAAC 4424 4443 458677 458696 3601 1371836 GAGTTGTCCATAGTCATGAA 4432 4451 458685 458704 3534 1371837 AAAGAAAAGTCAGGTATTTG 5509 5528 459762 459781 3332 1371838 GCCCTGACTAATTTCTTGGT 7042 7061 461295 461314 3581 1371839 ACAGAAACCAGCGTGGGTGT 4267 4286 458520 458539 3602 1371840 CTGACTAATTTCTTGGTGAT 7039 7058 461292 461311 3559 1371841 CCTCTTACCATCAAAGGCTA 5904 5923 460157 460176 2425 1371842 GCCCGTATTCCTCTTACCAT 5913 5932 460166 460185 2579 1371843 GCAGCCATCCAAGTAAGAAT 5477 5496 459730 459749 2578 1371844 TCATAATTCACATTCATCCC 4738 4757 458991 459010 2345 1371845 AGTTCATAATTCACATTCAT 4741 4760 458994 459013 2576 1371846 GTGTTCCATTGTAAACGCAA 7018 7037 461271 461290 123 1371847 ATTTTCTTTTTTCTGTGCCT N/A N/A 452653 452672 488 1371848 GGTCATTTATTGTCACATAC 4762 4781 459015 459034 194 1371849 TCCTCTTACCATCAAAGGCT 5905 5924 460158 460177 431 1371850 TGGGTGTTCGCTCTCTCCCT 4254 4273 458507 458526 270 1371851 ACCCGAGTTGTCCATAGTCA 4436 4455 458689 458708 582 1371852 CTGCACAGAAACCAGCGTGG 4271 4290 458524 458543 3603 1371853 CATAATTCACATTCATCCCT 4737 4756 458990 459009 3604 1371854 GCACCCGAGTTGTCCATAGT 4438 4457 458691 458710 3605 1371855 TTTTTCTTTTCGCCCTGACT 7053 7072 461306 461325 3606 1371856 ACTGCACAGAAACCAGCGTG 4272 4291 458525 458544 3607 1371857 TGTGTTCCATTGTAAACGCA 7019 7038 461272 461291 3608 1371858 CCTAACACTGCACAGAAACC 4278 4297 458531 458550 3609 1371859 TTTTATCCCAGTCATTGGCC N/A N/A 452682 452701 3610 1371860 CCAGTCATTGGCCCCCAAAC N/A N/A 452675 452694 3611 1371861 GGGTGTTCGCTCTCTCCCTC 4253 4272 458506 458525 3586 1371862 TTTTCTGTGCCTCCTGACCT N/A N/A 452645 452664 3612 1371863 GACCTCTACCCTTGTGAGCA N/A N/A 452630 452649 3613 1371864 CACTGCACAGAAACCAGCGT 4273 4292 458526 458545 3614 1371865 TTAATGAGAACAAAGTCTAT 5939 5958 460192 460211 3615 1371866 CATCCAAGTAAGAATATTTA 5472 5491 459725 459744 3616 1371867 AACACTGCACAGAAACCAGC 4275 4294 458528 458547 3617 1371868 AATGAGAACAAAGTCTATGT 5937 5956 460190 460209 3618 1371869 GCCATCCAAGTAAGAATATT 5474 5493 459727 459746 3619 1371870 TGTGGCAGCCCGTATTCCTC 5920 5939 460173 460192 3585 1371871 GTTGCAGCCATCCAAGTAAG 5480 5499 459733 459752 3620 1371872 CCGAGTTGTCCATAGTCATG 4434 4453 458687 458706 3621 1371873 CAAAGTCTATGTGGCAGCCC 5929 5948 460182 460201 3622 1371874 TAACACTGCACAGAAACCAG 4276 4295 458529 458548 3623 1371875 CCCGTATTCCTCTTACCATC 5912 5931 460165 460184 3590 1371876 CAGTTTAGTTGCAGCCATCC 5487 5506 459740 459759 3624 1371877 GTATTCCTCTTACCATCAAA 5909 5928 460162 460181 3589 1394164 TGTTCAGTTTAGTTGCAGCC 5491 5510 459744 459763 274 1394165 CCGTATTCCTCTTACCATCA 5911 5930 460164 460183 3588 1394166 TTCAGTTTAGTTGCAGCCAT 5489 5508 459742 459761 3190 1394167 TTGTTCAGTTTAGTTGCAGC 5492 5511 459745 459764 3655 1394168 GTTCAGTTTAGTTGCAGCCA 5490 5509 459743 459762 3577 1394522 GCCTTTATAACTTTTCTTTC N/A N/A 446680 446699 2552 1394523 GGTGGTCATTTATTGTCACA 4765 4784 459018 459037 3574 1394524 CAGCCCGTATTCCTCTTACC 5915 5934 460168 460187 509 1394525 GCTTCTCAAATCAGGTGTAC 8481 8500 462734 462753 1045 1394526 CCACGCTTTTATTTTCTGAT N/A N/A 439093 439112 2074 1394527 GTGGTCATTTATTGTCACAT 4764 4783 459017 459036 3560 1394528 ATGTGTTCTTAAATTCTCTA 8210 8229 462463 462482 1583 1394529 GCACGGTATTAGTGTCTTCA 7892 7911 462145 462164 126 1394530 GTTTGTTGGTTTCTTATTAA 7083 7102 461336 461355 46 1394531 CTGTATATTTATTACTTGAT 8228 8247 462481 462500 1891 1394532 CCTTGCACTTTTGTTTCTAC N/A N/A 441090 441109 321

The compounds in table 56 are 5-8-4 mixed MOE/cEt gapmers with mixed internucleoside linkages. The gapmers are 17 nucleosides in length, wherein the central gap segment consists of eight 2′-β-D-deoxynucleosides, the 5′ wing segment consists of five 2′-MOE nucleosides, and the 3′ wing segment consists of two cEt nucleosides and two 2′-MOE nucleosides. The sugar motif of the gapmers is (from 5′ to 3′): eeeeeddddddddkkee; wherein ‘d’ represents a 2′-P3-D-deoxyribosyl sugar moiety, ‘k’ represents a cEt sugar moiety, and ‘e’ represents a 2′-MOE sugar moiety. The gapmers have an internucleoside linkage motif of (from 5′ to 3′): sssosssssssssoss; wherein “s” represents a phosphorothioate internucleoside linkage and “o” represents a phosphodiester internucleoside linkage. All cytosine residues are 5-methylcytosines.

TABLE 56 5-8-4 MOE/cEt mixed wing gapmers with mixed PO/PS internucleoside linkages complementary to human ATXN1 SEQ ID SEQ ID SEQ ID SEQ ID No: 1 No: 1 No: 2 No: 2 Compound Start Stop Start Stop SEQ ID Number SEQUENCE Site Site Site Site No. 1365254 CACGCTTTTATTTTCTG N/A N/A 439095 439111 3625 1365255 CCACGCTTTTATTTTCT N/A N/A 439096 439112 3626 1365258 TTTATAACTTTTCTTTC N/A N/A 446680 446696 3627 1365259 CTTTATAACTTTTCTTT N/A N/A 446681 446697 3628 1365260 CCTTTATAACTTTTCTT N/A N/A 446682 446698 3629 1365261 GCCTTTATAACTTTTCT N/A N/A 446683 446699 3630 1365262 TCATTTATTGTCACATA 4763 4779 459016 459032 3631 1365263 CATTTATTGTCACATAC 4762 4778 459015 459031 3632 1365264 GTCATTTATTGTCACAT 4764 4780 459017 459033 3633 1365265 GGTCATTTATTGTCACA 4765 4781 459018 459034 3634 1365267 CCGAGTTGTCCATAGTC 4437 4453 458690 458706 3635 1365268 CCCGAGTTGTCCATAGT 4438 4454 458691 458707 3636 1365270 ACCCGAGTTGTCCATAG 4439 4455 458692 458708 3637 1365271 TCAGTTTAGTTGCAGCC 5491 5507 459744 459760 3638 1365272 CAGTTTAGTTGCAGCCA 5490 5506 459743 459759 3639 1365274 TTCAGTTTAGTTGCAGC 5492 5508 459745 459761 3640 1365275 TTCTTTTTTCTGTGCCT N/A N/A 452653 452669 3641

The compounds in table 57 are 5-8-4 mixed gapmers with mixed internucleoside linkages. The mixed gapmers, have mixed cEt/MOE wings and a 2′-OMe modified nucleoside at position 2 of the gap. The gapmers are 17 nucleosides in length, wherein the 5′ wing segment consists of five 2′-MOE nucleosides, the 3′ wing segment consists of two cEt nucleosides and two 2′-MOE nucleosides. The gap is eight nucleosides in length, and has a nucleoside comprising a 2′-β-D-deoxyribosyl sugar moiety at positions 1, 3, 4, 5, 6, 7, and 8 of the gap (counting from the 5′ end) and 2′-OMe nucleoside at position 2 of the gap (counting from the 5′ end). The sugar motif of the mixed gapmers is (from 5′ to 3′): eeeeedyddddddkkee; wherein ‘d’ represents a 2′-β-D-deoxyribosyl sugar moiety, ‘y’ represents a 2′-O-methyl ribose sugar moiety, ‘k’ represents a cEt sugar moiety, and ‘e’ represents a 2′-MOE sugar moiety. The gapmers have an internucleoside linkage motif of (from 5′ to 3′): sssosssssssssoss; wherein “s” represents a phosphorothioate internucleoside linkage and “o” represents a phosphodiester internucleoside linkage. All cytosine residues are 5-methylcytosines.

TABLE 57 5-8-4 MOE/cEt mixed gapmers with mixed PO/PS internucleoside linkages complementary to human ATXN1 SEQ ID SEQ ID Compound No: 1 Start No: 1 Stop SEQ ID No: SEQ ID No: SEQ Number SEQUENCE Site Site 2 Start Site 2 Stop Site ID No. 1365278 CGCTTTUATTTTCTGAT N/A N/A 439093 439109 3642 1365281 CCACGCUTTTATTTTCT N/A N/A 439096 439112 3643 1365282 TTTATAACTTTTCTTTC N/A N/A 446680 446696 3627 1365283 CCTTTAUAACTTTTCTT N/A N/A 446682 446698 3644 1365284 GCCTTTATAACTTTTCT N/A N/A 446683 446699 3630 1365285 CATTTAUTGTCACATAC 4762 4778 459015 459031 3645 1365286 TCATTTATTGTCACATA 4763 4779 459016 459032 3631 1365287 CTTTATAACTTTTCTTT N/A N/A 446681 446697 3628 1365288 GTCATTUATTGTCACAT 4764 4780 459017 459033 3646 1365289 GGTCATUTATTGTCACA 4765 4781 459018 459034 3647 1365290 CCGAGTUGTCCATAGTC 4437 4453 458690 458706 3648 1365291 CGAGTTGTCCATAGTCA 4436 4452 458689 458705 3649 1365292 ACCCGAGTTGTCCATAG 4439 4455 458692 458708 3637 1365293 TTTCTTUTTTCTGTGCC N/A N/A 452654 452670 3650 1365294 CAGTTTAGTTGCAGCCA 5490 5506 459743 459759 3639 1365297 TTCTTTUTTCTGTGCCT N/A N/A 452653 452669 3651 1365298 CCCGAGUTGTCCATAGT 4438 4454 458691 458707 3652 1365299 TTCAGTUTAGTTGCAGC 5492 5508 459745 459761 3653 1365300 TCAGTTUAGTTGCAGCC 5491 5507 459744 459760 3654

The compounds in table 58 are 5-8-4 MOE gapmers with mixed internucleoside linkages. The gapmers are 17 nucleosides in length, wherein the central gap segment consists of eight 2′-β-D-deoxynucleosides, the 5′ wing segment consists of five 2′-MOE nucleosides, and the 3′ wing segment consists of four 2′-MOE nucleosides. The sugar motif of the gapmers is (from 5′ to 3′): eeeeeddddddddeeee; wherein ‘d’ represents a 2′-β-D-deoxyribosyl sugar moiety, and ‘e’ represents a 2′-MOE sugar moiety. The gapmers have an internucleoside linkage motif of (from 5′ to 3′): sssosssssssssoss; wherein “s” represents a phosphorothioate internucleoside linkage and “o” represents a phosphodiester internucleoside linkage. All cytosine residues are 5-methylcytosines.

TABLE 58 5-8-4 MOE gapmers with mixed PO/PS internucleoside linkages complementary to human ATXN1 SEQ SEQ SEQ SEQ ID No: ID No: ID No: ID No: Compound 1 Start 1 Stop 2 Start 2 Stop Number SEQUENCE Site Site Site Site SEQ ID No. 1385293 TCAGTTTAGTTGCAGCC 5491 5507 459744 459760 3638 1385294 GGTCATTTATTGTCACA 4765 4781 459018 459034 3634 1385295 CCGAGTTGTCCATAGTC 4437 4453 458690 458706 3635 1394533 CAGTTTAGTTGCAGCCA 5490 5506 459743 459759 3639 1394534 CGAGTTGTCCATAGTCA 4436 4452 458689 458705 3649 1394537 GCACCCGAGTTGTCCAT 4441 4457 458694 458710 3656 1394538 CAGCCCGTATTCCTCTT 5918 5934 460171 460187 3657 1394539 CACCCGAGTTGTCCATA 4440 4456 458693 458709 3658 1394540 GAGTTGTCCATAGTCAT 4435 4451 458688 458704 3659 1394541 CCCGTATTCCTCTTACC 5915 5931 460168 460184 3660 1394543 AGCCCGTATTCCTCTTA 5917 5933 460170 460186 3661 1394544 AGTTTAGTTGCAGCCAT 5489 5505 459742 459758 3662 1394545 GTATTCCTCTTACCATC 5912 5928 460165 460181 3663 1394546 TTCAGTTTAGTTGCAGC 5492 5508 459745 459761 3640 1394547 CCCGAGTTGTCCATAGT 4438 4454 458691 458707 3636 1394548 CGTATTCCTCTTACCAT 5913 5929 460166 460182 3664 1394549 TGTTCAGTTTAGTTGCA 5494 5510 459747 459763 3665 1394550 TATTCCTCTTACCATCA 5911 5927 460164 460180 3666 1394551 CCGTATTCCTCTTACCA 5914 5930 460167 460183 3667 1394552 GCCCGTATTCCTCTTAC 5916 5932 460169 460185 3668 1394553 TTGTTCAGTTTAGTTGC 5495 5511 459748 459764 3669

The compounds in table 59 are 5-10-5 MOE gapmers with mixed internucleoside linkages. The gapmers are 20 nucleosides in length, wherein the central gap segment consists often 2′-β-D-deoxynucleosides, the 5′ wing segment consists of five 2′-MOE nucleosides, and the 3′ wing segment consists of five 2′-MOE nucleosides. The sugar motif of the gapmers is (from 5′ to 3′): eeeeeddddddddddeeeee; wherein ‘d’ represents a 2′-β-D-deoxyribosyl sugar moiety, and ‘e’ represents a 2′-MOE sugar moiety. The gapmers have an internucleoside linkage motif of (from 5′ to 3′): sooosssssssssssooss; wherein “s” represents a phosphorothioate internucleoside linkage and “o” represents a phosphodiester internucleoside linkage. All cytosine residues are 5-methylcytosines.

TABLE 59 5-10-5 MOE gapmers with mixed PO/PS internucleoside linkages complementary to human ATXN1 SEQ ID SEQ ID SEQ ID SEQ ID Compound No: 1 No: 1 No: 2 Start No: 2 Stop SEQ Number SEQUENCE Start Site Stop Site Site Site ID No. 1371311 CCCGTATTCCTCTTACCATC 5912 5931 460165 460184 3590 1371320 TGTGGCAGCCCGTATTCCTC 5920 5939 460173 460192 3585 1371322 CACCCGAGTTGTCCATAGTC 4437 4456 458690 458709 3593 1371325 GCACCCGAGTIGTCCATAGT 4438 4457 458691 458710 3605 1394162 TTGTTCAGTTTAGTTGCAGC 5492 5511 459745 459764 3655 1394163 CCGTATTCCTCTTACCATCA 5911 5930 460164 460183 3588

Example 5: Tolerability of Modified Oligonucleotides Complementary to Human ATXN1 in Rats, Long-Term Assessment

In separate studies run under the same conditions, modified oligonucleotides described above were tested in Sprague Dawley rats to assess the long-term tolerability of the oligonucleotides. Sprague Dawley rats each received a single intrathecal (IT) delivered dose of 3 mg of oligonucleotide or PBS. Each animal was weighed and evaluated weekly by a trained observer for adverse events. Adverse events were defined as neurological dysfunction not typical in PBS-treated control animals, including, but not limited to: abnormal limb splay, abnormal gait, tremors, abnormal respiration, paralysis, and spasticity. Animals treated with Compound No. 994509, Compound No. 1040500, Compound No. 1041927, Compound No. 1055001, Compound No. 1371311, or Compound No. 1385293 achieved no adverse events for the duration of the study.

Example 6: Activity of Modified Oligonucleotides Complementary to Human ATXN1 in Transgenic Mice

A transgenic mouse model was developed in the laboratories of Drs. Harry Orr and Michael Koob at the University of Minnesota. The construct contains human Atxn1 exon 8, intron 8 and exon 9 including the entire 3′ UTR (Banfi et al. Nat. Genet. 7: 513-520, 1994) (including nucleosides 435531-464889 of SEQ ID NO:2) flanked by Frt sites for FLP recombinase and the selection marker Hygro flanked by LoxN sites for CRE recombinase. The construct was injected into mouse blastocysts. The human sequence of exon 8, intron 8 and exon 9 replace the mouse Atxn1 exon 7, intron 7, and exon 8. The Hygro cassette was removed via recombination to generate chimeric mice expressing human coding sequence exon 8 and exon 9. Human RNA expression is found in brain and spinal cord in this model. There is a one base deletion causing a stop codon at amino acid 190, so protein is not generated.

Transgenic mice described above were used to test activity of modified oligonucleotides described above.

Treatment

ATXN1 transgenic mice were treated with a single ICV bolus of 300 μg of modified oligonucleotide. A group of 3-4 mice received PBS as a negative control on each treatment day, and the PCR values were normalized to the PBS control group for mice treated on the same day. In some cases, individual mice treated with a given modified oligonucleotide were treated on different days, and the reported results for each modified oligonucleotide in the table below represent the average across 1-3 independent experiments representing 1-5 treated mice for each modified oligonucleotide.

RNA Analysis

Two weeks post treatment, mice were sacrificed, and RNA was extracted from cortical brain tissue for real-time qPCR analysis of RNA expression of ATXN1 using primer probe set RTS37573 (described herein above). Results are presented as percent change of RNA, relative to PBS control, normalized to mouse cyclophilin A. Data indicated as “n.d.” (no data) means that no data are available for that tissue for that compound.

As shown in the table below, treatment with modified oligonucleotides resulted in reduction of ATXN1 RNA in comparison to the PBS control.

TABLE 60 Reduction of human ATXN1 RNA in transgenic mice ATXN1 Compound RNA Number (% control) 994334 88 994341 80 994346 74 994351 51 994366 99 994367 83 994374 82 994375 88 994398 30 994408 72 994409 80 994413 18 994417 95 994418 54 994419 28 994421 15 994424 62 994429 63 994430 36 994434 63 994437 22 994442 76 994443 62 994447 52 994448 62 994449 58 994453 58 994458 24 994459 36 994460 50 994464 49 994465 65 994467 59 994468 43 994469 32 994484 50 994485 90 994486 37 994491 51 994492 37 994493 19 994494 26 994495 48 994501 69 994502 67 994503 63 994506 56 994507 73 994508 81 994509 33 994517 89 994518 45 994520 48 994522 55 994526 36 994527 38 994539 63 994540 44 994541 82 994543 91 994545 59 994559 84 994561 65 994562 57 994564 73 994567 81 994569 46 994571 75 994809 57 994810 50 994811 43 994813 66 994819 46 994823 42 994829 86 994831 91 994836 94 994840 71 994841 67 994854 89 994856 72 994857 73 994859 78 994874 88 994876 81 994877 42 994878 92 994885 61 994887 71 994895 52 994904 33 994906 68 994913 18 994921 51 994925 91 1040083 83 1040084 39 1040085 48 1040092 62 1040107 104 1040109 59 1040146 55 1040151 64 1040170 56 1040173 94 1040180 93 1040191 108 1040198 107 1040199 69 1040203 75 1040207 75 1040213 85 1040223 60 1040227 80 1040231 56 1040236 91 1040237 59 1040238 79 1040239 72 1040248 82 1040297 63 1040299 48 1040328 17 1040329 32 1040334 84 1040335 90 1040337 51 1040338 66 1040389 92 1040413 81 1040435 81 1040438 75 1040442 85 1040472 93 1040475 44 1040479 27 1040500 38 1040502 84 1040512 49 1040514 74 1040597 92 1040601 72 1041318 49 1041319 88 1041326 82 1041328 51 1041334 90 1041339 90 1041345 87 1041355 63 1041366 71 1041390 41 1041398 48 1041400 72 1041406 98 1041409 37 1041413 62 1041425 69 1041429 65 1041433 73 1041434 103 1041438 85 1041439 66 1041441 86 1041443 101 1041455 77 1041469 75 1041471 48 1041486 48 1041489 101 1041498 43 1041527 95 1041532 85 1041537 87 1041548 98 1041550 114 1041557 83 1041567 71 1041575 103 1041597 119 1041603 96 1041605 82 1041608 76 1041623 64 1041636 70 1041649 94 1041653 84 1041676 91 1041679 88 1041682 103 1041699 75 1041729 79 1041733 113 1041736 72 1041746 42 1041757 66 1041768 63 1041769 47 1041776 99 1041777 86 1041927 37 1042257 105 1042471 60 1055001 27 1055004 34 1055006 46 1055007 34 1055012 63 1055013 76 1055014 50 1055017 92 1055020 71 1055025 95 1055027 73 1055035 68 1055046 98 1055050 73 1342029 49 1342030 107 1342031 80 1342032 48 1342033 77 1342034 92 1342035 89 1342036 60 1342037 89 1342038 63 1342039 86 1342040 117 1342041 58 1342042 80 1342043 95 1342044 78 1342045 101 1342046 83 1342047 86 1342048 64 1342049 88 1342050 107 1342051 80 1342052 98 1342053 87 1342054 106 1342055 97 1342056 86 1342057 99 1342058 55 1342059 97 1342060 107 1342061 86 1342062 73 1342063 68 1342064 68 1342065 76 1342066 98 1342067 25 1342068 58 1342069 83 1342070 94 1342071 88 1342072 82 1342073 77 1342074 74 1342075 43 1342076 86 1342077 69 1364280 36 1364281 48 1364282 41 1364283 26 1364285 29 1365254 65 1365255 62 1365258 123 1365259 121 1365260 94 1365261 49 1365262 76 1365263 69 1365264 43 1365265 34 1365267 44 1365268 44 1365270 49 1365271 28 1365272 38 1365274 46 1365275 51 1365278 81 1365281 71 1365282 92 1365283 83 1365284 92 1365285 76 1365286 79 1365287 61 1365288 71 1365289 72 1365290 69 1365291 55 1365292 45 1365293 94 1365294 65 1365297 96 1365298 53 1365299 75 1365300 51 1367569 80 1367572 53 1367573 44 1367575 99 1367576 89 1367577 52 1367580 46 1367581 42 1367586 66 1367588 59 1367589 19 1367590 80 1367591 21 1371311 24 1371320 66 1371322 79 1371325 48 1371806 52 1371807 70 1371808 78 1371809 62 1371810 50 1371811 74 1371812 89 1371813 112 1371814 70 1371815 76 1371816 51 1371817 62 1371818 35 1371819 49 1371820 68 1371821 62 1371822 60 1371823 90 1371824 60 1371825 29 1371826 70 1371827 59 1371828 63 1371829 32 1371830 60 1371831 86 1371832 84 1371833 81 1371834 89 1371835 92 1371836 111 1371837 96 1371838 90 1371839 81 1371840 87 1371841 83 1371842 29 1371843 71 1371844 59 1371845 73 1371846 62 1371847 82 1371848 38 1371849 72 1371850 78 1371851 49 1371852 89 1371853 66 1371854 37 1371855 36 1371856 77 1371857 76 1371858 104 1371859 94 1371860 98 1371861 86 1371862 75 1371863 68 1371864 81 1371865 87 1371866 58 1371867 83 1371868 85 1371869 70 1371870 46 1371871 60 1371872 56 1371873 78 1371874 77 1371875 17 1371876 39 1371877 48 1385293 31 1385294 25 1385295 27 1394153 41 1394154 65 1394155 49 1394156 40 1394157 30 1394158 33 1394159 24 1394160 30 1394161 29 1394162 45 1394163 35 1394164 42 1394165 43 1394166 43 1394167 28 1394168 33 1394507 46 1394508 63 1394510 66 1394511 77 1394512 54 1394513 38 1394514 73 1394515 87 1394516 72 1394517 91 1394518 73 1394522 40 1394523 86 1394524 32 1394525 43 1394526 8 1394527 68 1394528 71 1394529 38 1394530 38 1394531 65 1394532 42 1394533 38 1394534 66 1394537 45 1394538 54 1394539 58 1394540 59 1394541 67 1394543 46 1394544 43 1394545 66 1394546 26 1394547 53 1394548 88 1394549 51 1394550 92 1394551 48 1394552 33 1394553 85

Example 7: Activity of Modified Oligonucleotides Complementary to Human ATXN1 in Transgenic Mice, Multiple Doses

Modified oligonucleotides described above were tested in the ATXN1 transgenic mice described herein above.

Treatment

ATXN1 transgenic mice were divided into groups of 3-4 mice each. Each mouse received a single ICV bolus of modified oligonucleotide at the doses described in the tables below and were sacrificed two weeks later. A group of 4 mice received PBS as a negative control for each experiment. Each table represents a separate experiment.

RNA Analysis

After two weeks, mice were sacrificed, and RNA was extracted from cortical brain tissue for real-time PCR analysis of measurement of RNA expression of ATXN1 using primer probe set RTS37573. Results are presented as percent change of RNA, relative to PBS control, normalized to mouse cyclophilin A (measured by primer-probe set m_cyclo24 described herein above). ED50 values were calculated in GraphPad Prism. N/A means that an ED50 value could not be reliably calculated for that experiment.

As shown in the tables below, treatment with modified oligonucleotides resulted in dose-dependent reduction of ATXN1 RNA in comparison to the PBS control.

TABLE 61 Dose-dependent percent reduction of human ATXN1 RNA in the cortex of transgenic mice Compound Dose ATXN1 RNA ED50 ID (μg) (% control) (μg) 1040479 10 97 669.1 30 86 100 87 300 59 700 51 1040500 10 87 126.2 30 83 100 59 300 44 700 22 1367591 10 80 40.59 30 66 100 32 300 23 700 22 1371311 10 76 36.11 30 57 100 45 300 19 700 14 1371875 10 70 30.41 30 67 100 25 300 12 700 9 1394161 10 71 36.04 30 68 100 35 300 18 700 8

TABLE 62 Dose-dependent percent reduction of human ATXN1 RNA in transgenic mice Cortex Compound Dose ATXN1 RNA ED50 ID (μg) (% control) (μg) 1041409 10 94 277.3 30 88 100 78 300 56 700 34 1055001 10 91 144 30 89 100 75 300 23 700 18 1055007 10 104 156.9 30 88 100 75 300 31 700 22 1371827 10 92 87.95 30 77 100 50 300 34 700 22

TABLE 63 Dose-dependent percent reduction of human ATXN1 RNA in transgenic mice Cortex Compound Dose ATXN1 RNA ED50 ID (μg) (% control) (μg) 994823 10 110 308.3 30 96 100 72 300 64 700 32 1385293 10 90 93.14 30 75 100 63 300 25 700 15

TABLE 64 Dose-dependent percent reduction of human ATXN1 RNA in transgenic mice Cortex Compound Dose ATXN1 RNA ED50 ID (μg) (% control) (μg) 994492 10 78 72.25 30 72 100 52 300 41 700 22 994509 10 80 27.84 30 53 100 30 300 20 700 17

TABLE 65 Dose-dependent percent reduction of human ATXN1 RNA in transgenic mice Cortex Compound Dose ATXN1 RNA ED50 ID (μg) (% control) (μg) 1041927 10 72 52.22 30 71 100 41 300 29 700 33 994419 10 83 50.14 30 65 100 46 300 22 700 17 1394155 10 72 105.4 30 70 100 60 300 41 700 40 

The invention claimed is:
 1. A modified oligonucleotide according to the following chemical structure:

salt thereof.
 2. The modified oligonucleotide of claim 1, which is the sodium salt or the potassium salt.
 3. A modified oligonucleotide according to the following chemical structure:


4. An oligomeric compound comprising a modified oligonucleotide according to the following chemical notation: ^(m)Ces ^(m)Ceo ^(m)Ceo Geo Tes Ads Tds Tds ^(m)Cds ^(m)Cds Tds ^(m)Cds Tds Tds Ads ^(m)Ceo ^(m)Ceo Aes Tes ^(m)Ce (SEQ ID NO: 3590), wherein, A=an adenine nucleobase, ^(m)C=a 5-methylcytosine nucleobase, G=a guanine nucleobase, T=a thymine nucleobase, e=a 2′-MOE sugar moiety, d=a 2′-β-D deoxyribosyl sugar moiety, s=a phosphorothioate internucleoside linkage, and o=a phosphodiester internucleoside linkage.
 5. A population of modified oligonucleotides of claim 1, wherein all of the phosphorothioate internucleoside linkages of the modified oligonucleotides are stereorandom.
 6. A population of modified oligonucleotides of claim 2, wherein all of the phosphorothioate internucleoside linkages of the modified oligonucleotides are stereorandom.
 7. A population of modified oligonucleotides of claim 3, wherein all of the phosphorothioate internucleoside linkages of the modified oligonucleotides are stereorandom.
 8. A population of oligomeric compounds of claim 4, wherein all of the phosphorothioate internucleoside linkages of the modified oligonucleotides are stereorandom.
 9. A pharmaceutical composition comprising the modified oligonucleotide of claim 1, and a pharmaceutically acceptable diluent.
 10. The pharmaceutical composition of claim 9, wherein the pharmaceutically acceptable diluent is phosphate-buffered saline (PBS) or artificial cerebrospinal fluid.
 11. The pharmaceutical composition of claim 10, wherein the pharmaceutical composition consists essentially of the modified oligonucleotide and artificial cerebrospinal fluid.
 12. The pharmaceutical composition of claim 10, wherein the pharmaceutical composition consists essentially of the modified oligonucleotide and PBS.
 13. A pharmaceutical composition comprising the modified oligonucleotide of claim 2, and a pharmaceutically acceptable diluent.
 14. The pharmaceutical composition of claim 13, wherein the pharmaceutically acceptable diluent is phosphate-buffered saline (PBS) or artificial cerebrospinal fluid.
 15. The pharmaceutical composition of claim 14, wherein the pharmaceutical composition consists essentially of the modified oligonucleotide and artificial cerebrospinal fluid.
 16. The pharmaceutical composition of claim 14, wherein the pharmaceutical composition consists essentially of the modified oligonucleotide and PBS.
 17. A pharmaceutical composition comprising the modified oligonucleotide of claim 3, and a pharmaceutically acceptable diluent.
 18. The pharmaceutical composition of claim 17, wherein the pharmaceutically acceptable diluent is phosphate-buffered saline (PBS) or artificial cerebrospinal fluid.
 19. The pharmaceutical composition of claim 18, wherein the pharmaceutical composition consists essentially of the modified oligonucleotide and artificial cerebrospinal fluid.
 20. The pharmaceutical composition of claim 18, wherein the pharmaceutical composition consists essentially of the modified oligonucleotide and PBS.
 21. A pharmaceutical composition comprising the oligomeric compound of claim 4, and a pharmaceutically acceptable diluent.
 22. The pharmaceutical composition of claim 21, wherein the pharmaceutically acceptable diluent is phosphate-buffered saline (PBS) or artificial cerebrospinal fluid.
 23. The pharmaceutical composition of claim 22, wherein the pharmaceutical composition consists essentially of the oligomeric compound and artificial cerebrospinal fluid.
 24. The pharmaceutical composition of claim 22, wherein the pharmaceutical composition consists essentially of the oligomeric compound and PBS.
 25. A pharmaceutical composition comprising the population of modified oligonucleotides of claim 5, and a pharmaceutically acceptable diluent.
 26. The pharmaceutical composition of claim 25, wherein the pharmaceutically acceptable diluent is phosphate-buffered saline (PBS) or artificial cerebrospinal fluid.
 27. A pharmaceutical composition comprising the population of modified oligonucleotides of claim 7, and a pharmaceutically acceptable diluent.
 28. The pharmaceutical composition of claim 27, wherein the pharmaceutically acceptable diluent is phosphate-buffered saline (PBS) or artificial cerebrospinal fluid.
 29. A pharmaceutical composition comprising the population of oligomeric compounds of claim 8, and a pharmaceutically acceptable diluent.
 30. The pharmaceutical composition of claim 29, wherein the pharmaceutically acceptable diluent is phosphate-buffered saline (PBS) or artificial cerebrospinal fluid. 